Apelin receptor (apj) agonists and uses thereof

ABSTRACT

This disclosure is directed to agonists of the apelin receptor (APJ) and uses of such agonists.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Prov. Appn. 62/265,168 filedDec. 9, 2015, Runyon et al., entitled “Improved Apelin Receptor (APJ)Agonists and Uses Thereof” and U.S. Prov. Appn. 62/265,177 filed Dec. 9,2015, Runyon et al., entitled “Difluoro Apelin Receptor (APJ) Agonistsand Uses Thereof” which are hereby incorporated by reference in theirentireties.

1. FIELD

This disclosure relates generally to the discovery of agonists of theapelin receptor (APJ) and uses of such agonists.

2. BACKGROUND

2.1. Introduction: Apelin and the Apelin Receptor (APJ)

The apelin receptor (APJ) was cloned in 1993 as an orphan G-proteincoupled receptor (GPCR). The human APJ gene is located on the long armof chromosome 11 and encodes a 377 amino acid G protein-coupledreceptor. The gene for APJ was designated angiotensin-receptor like 1(AGTRL1) due to sequence similarities between the two receptors. Carpeneet al., J Physiol Biochem. 2007; 63(4):359-373. However, none of theknown peptidergic ligands for the angiotensin receptors, includingangiotensin, activate APJ. APJ remained an orphan GPCR until 1998 whenthe peptide apelin was identified as its endogenous ligand. Lee et al.,J Neurochem. 2000; 74(1):34-41; Habata et al., Biochim Biophys Acta.1999; 1452(1):25-35.

Over the years, apelin and APJ have emerged as an important regulator ofvarious physiological processes. Both apelin and APJ are expressed inthe central nervous system (CNS) and peripherally in a number oftissues. Expression of APJ has been noted within the vasculature of someorgans and is a potent regulator of related processes includingangiogenesis and vasoconstriction. Cobellis et al. report increased ofexpression levels of both apelin and APJ receptor inpreeclampsia-complicated pregnancies. Cobellis et al., HistolHistopathol. 2007; 22(1):1-8. APJ is also expressed in nonvascular celltypes in heart, liver, and CNS where its primary role is currently underinvestigation. Medhurst et al., J Neurochem. 2003; 84(5):1162-1172.Apelin and APJ are often co-localized within the same organ suggestingan autocrine regulation of the receptor by its ligand. However, apelinhas since been detected in blood suggesting that concomitant paracrineregulation of the receptor is also possible. The apelin—APJ system hasbeen implicated as a regulator of various physiological functions and isbelieved to play an important role in thermoregulation, immunity,glucose metabolism, angiogenesis, fluid homeostasis, cardiac function,hepatic function and renal function. Ladeiras-Lopes et al., Arq BrasCardiol. 2008; 90(5):343-349. APJ also acts as a co-receptor during HIVinfection. O'Donnell et al., J Neurochem. 2007; 102(6):1905-1917; Zou etal., FEBS Lett. 2000; 473(1):15-18.

Expression of apelin and APJ are either up- or down-regulated in variouspathophysiological conditions. In particular, the APJ appears to be anemerging target for the treatment of cardiovascular failure, liverfibrosis, cancer, angiopathies, pancreatitis, and as a prophylacticagainst HIV infection. In 2011 Andersen et al. reviewed apelin and APJas an opportunity for therapeutic uses for pulmonary hypertension andpulmonary arterial hypertension (PAH). Andersen et al. Pulm. Circ. 2011;1(3) 334-346.

Unfortunately, small molecule ligands of the APJ having suitablepharmacological properties are lacking. Few nonpeptide ligand systemshas been reported to date. Iturrioz et al. report compounds that containpolycyclic fluorophores, such as lissamine, which make them ill-suitedfor pharmaceutical uses. Iturrioz et al., FASEB J. 2010; 24:1506-1517;EP 1903052 (Llorens-Cortes et al.). US Publ. Pat. Appn. 2014/0094450(Hachtel et al.) discloses benzoimidazole-carboxylic acid amidederivatives as APJ receptor modulators.

Accordingly, there is a need for small molecule agonists of APJ.

3. SUMMARY OF THE DISCLOSURE

This disclosure provides a compound represented by the Formula I:

or a pharmaceutically acceptable salt, a prodrug, or a salt of aprodrug,

-   wherein R₁ is represented by the formula:

wherein

is a monocyclic aryl or heteroaryl group; each A is independently C₁₋₈alkyl, C₁₋₈ alkyl(aryl), C₁₋₈ alkoxy, C₁₋₈ alkoxy aryl, C₂₋₈ alkenyl,C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, —CF₃, —(CH₂)_(x)NR₇R₈, —CN, —CONR₇R₈,—COR₇, —CO₂(CH₂)_(x)NR₇R₈, —CO₂R₇, halogen, hydroxyl, —N₃, —NHCOR₇,—NHSO₂C₁₋₈ alkyl, —NHCO₂C₁₋₈ alkyl, —NO₂, —NR₇R₈, —O(CH₂)_(x)NR₇R₈,—O(CH₂)_(x)CO₂R₇, —OCOC₁₋₈alkyl, —OCO(CH₂)_(x)NR₇R₈, —SF₅, —SO₂NR₇R₈,—SO₍₁₋₃₎R₇, —SR₇, or tetrazolone; R₇ and R₈ are independently C₁₋₈alkoxy, aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈alkyl amido, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyltetrazol-5-one, C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkylthioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈cycloalkyl, —(CH₂)_(x)CONHR₉, —(CH₂)_(x)COR₉, —(CH₂)_(x)CO₂R₉, H, orheteroaryl; or R₇ and R₈ together make a 3-9 member ring which maycontain one or more heteroatoms; or R₇ and R₈ together make a 5-8nitrogen containing member ring with one or more carbonyl groups; n is1, 2, 3, 4 or 5; R₂ is C₃₋₈ alkyl, C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₃₋₈cycloalkyl, heteroaryl, or substituted aryl; R₄, R₅ and R₆ areindependently adamantanyl, aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈alkyl amino, C₁₋₈ alkyl amido, C₂₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈cycloalkyl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl)-CO₂R₇, C₁₋₈ alkyl guanidinyl,C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl tetrazol-5-one, C₂₋₄ alkylheterocycloalkyl, C₁₋₈ alkyl thioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl,C₂₋₈ alkenyl(aryl), C₂₋₈ alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-CO₂R₇, —(CH₂)_(x)NR₇R₈, —(CH₂)_(x)OR₇,—(CH₂)_(x)NR₉COR₇, —(CH₂)_(x)NR₉S02R₇, —(CH₂)_(x)N R₉CO₂R₇,—(CH₂)_(x)NHCOR₇, —(CH₂)_(x)NHSO₂R₇, —(CH₂)_(x)NHCO₂R₇,—(CH₂)_(x)CONR₇R₈, —(CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉,—(CH₂)_(x)CONR₇(CH₂)_(y)CONR₇R₈, —(CH₂)_(x)CONR₇(CH₂)_(y)R₉,—(CH₂)_(x)COR₇, —(CH₂)_(x)CO₂R₇, —(CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉, —CHR₇COR₉,—CHR₇CONHCHR₈COR₉, —CONR₇R₈, —CONR₇(CH₂)_(x)CO₂R₈, —CONR₇CHR₈CO₂R₉,—CO₂R₉, H, or —NHCO₂R₇, —(CH₂)_(x)SO₂NR₇R₈; —SF₅; or R₄ and R₅ togethermake a 4-8 member ring which may be substituted with one or moreheteroatoms; or R₄ and R₅ together make a 5-8 nitrogen containing memberring with one or more carbonyl groups; wherein the group R₄ issubstituted with one or more fluorine atoms; R₉ is aryl, C₁₋₈ alkoxy,C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₃₋₈ cycloalkyl, H, heteroaryl, orhydroxyl; each x is independently 0-8; and each y is independently 1-8.

The disclosure also provides a compound represented by the Formula II:

or a pharmaceutically acceptable salt, a prodrug, or a salt of aprodrug,

-   wherein R₁ is represented by the formula:

wherein

is a monocyclic heteroaryl group; each A is independently C₁₋₈ alkyl,C₁₋₈ alkyl(aryl), C₁₋₈ alkoxy, C₁₋₈ alkoxy aryl, C₂₋₈ alkenyl, C₃₋₈alkynyl, C₃₋₈ cycloalkyl, —CF₃, —(CH₂)_(x)NR₇R₈, —CN, —CONR₇R₈, —COR₇,—CO₂(CH₂)_(x)NR₇R₈, —CO₂R₇, halogen, hydroxyl, —N₃, —NHCOR₇,—NHSO₂C₁₋₈alkyl, —NHCO₂C₁₋₈alkyl, —NO₂, —NR₇R₈, —O(CH₂)_(x)NR₇R₈,—O(CH₂)_(x)CO₂R₇, —OCOC₁₋₈ alkyl, —OCO(CH₂)_(x)NR₇R₈, —SF₅, —SO₂NR₇R₈,—SO₁₋₃₎R₇, or —SR_(7;) each R₇ and R₈ are independently C₁₋₈ alkoxy,aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkylamido, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkylguanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl thioether, C₁₋₈ alkylthiol, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, —(CH₂)_(x)CONHR₉,—(CH₂)_(x)COR₉, —(CH₂)_(x)CO₂R₉, H, or heteroaryl; or R₇ and R₈ togethermake a 3-9 member cycloalkyl or heterocycloalkyl group; n is 1, 2, 3, 4or 5; each x is independently 0-8;

-   R₂ is present or absent, and if present, is C₃₋₈ alkyl, C₁₋₈ alkyl    (C₃₋₈ cycloalkyl), C₃₋₈ cycloalkyl, heteroaryl, or substituted aryl;-   R₃ is present or absent, is absent if R₂ is present, and if present    is C₁₋₈ alkyl, C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₃₋₈ cycloalkyl or    substituted aryl;-   R₄, R₅, and R₆ are independently adamantanyl, aryl, C₁₋₈ alkyl, C₁₋₈    alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₂₋₈ alkyl(aryl),    C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl)-CO₂R₇,    C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl    tetrazol-5-one, C₂₋₄ alkyl C₆ heterocycloalkyl, C₁₋₈ alkyl    thioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl), C₂₋₈    alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₉ cycloalkyl, C₃₋₈    cycloalkyl-CO₂R₇, —(CH₂)_(x)NR₇R₈, —(CH₂)_(x)OR₇, —(CH₂)_(x)NHCOR₇,    —(CH₂)_(x)NHSO₂R₇, —(CH₂)_(x)NHCO₂R₇, —(CH₂)_(x)CONR₇R₈,    —(CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉, —(CH₂)_(x)CONR₇(CH₂)_(y)CONR₈R₉,    —(CH₂)_(x)CONR₇(CH₂)_(y)R₉, —(CH₂)_(x)CONR₇(CH₂)_(y)SO₂R₉,    —(CH₂)_(x)COR₇, —(CH₂)_(x)CO₂R₇,    —(CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉,—CHR₇COR₉ —CHR₇CONHCHR₈COR₉ , —CONR₇R₈,    —CONR₇(CH₂)_(x)CO₂R₈, —CONR₇CHR₈CO₂R₉, —CO₂R₉, H, —NHCO₂R₇, —SF₅,    —SO₂NR₇R₈, or R₄ and R₅ together make a 4-9 member cycloalkyl or    heterocycloalkyl group; wherein the group R₄ is substituted with one    or more fluorine atoms; R₉ is aryl, C₁₋₈ alkoxy, C₁₋₈ alkyl, C₁₋₈    alkyl(aryl), C₃₋₈ cycloalkyl, H, heteroaryl, or hydroxyl; and each y    is independently 1-8.

Furthermore, the disclosure provides a compound of par. [0008],represented by Formula III

wherein n is 1, 2 or 3; each A is independently C₁-C₅ alkoxy, C₁-C₅alkyl, C₃₋₈ cycloalkyl, halogen, or —SF₅; R₂ is C₃-C₆ alkyl, C₁₋₃ alkyl(C₃₋₆ cycloalkyl) or C₃-C₇ cycloalkyl;

-   R₄ is aryl, C₁₋₄ alkyl, C₂₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈    cycloalkyl), C₁₋₈ alkyl heteroaryl, C₂₋₄ alkyl C₆ heterocycloalkyl,    C₂₋₈ alkenyl(aryl), C₂₋₈ alkenyl(heteroaryl), or heteroaryl; wherein    the group R₄ is substituted with one or more fluorine atoms; and-   R₁₀ is aryl, C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈    cycloalkyl), C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl tetrazol-5-one, C₃₋₈    cycloalkyl, or heteroaryl.

The disclosure provides the compound of any of par. [0008]-[0010],wherein each A is independently C₁-C₃ alkoxy, C₁-C₃ alkyl, chloro, orfluoro. In one embodiment, each A is independently fluoro substitutedC₁-C₃ alkoxy or fluoro substituted C₁-C₃ alkyl.

The disclosure provides the compound of any of par. [0008]-[0011],wherein R₂ is —C₄H₉, —C₅H₁₁, -cC₄H₈ or —cC₅H₁₀.

The disclosure provides the compound of any of par. [0008]-[0012],wherein the R₄ group contains a nitrogen and two or more fluorine atoms.

The disclosure provides the compound of any of par. [0008]-[0013],wherein R₄ is C₁₋₈ alkyl(aryl), C₁₋₄ alkyl cycloalkyl, C₁₋₈ alkylheteroaryl, C₁₋₄ alkyl heterocycloalkyl, C₂₋₈ alkenyl(aryl), or C₂₋₈alkenyl(heteroaryl). The cycloalkyl group in the C₁₋₄ alkyl cycloalkylmay be a bicycloalkyl or a spiroalkyl group or the heterocycloalkylgroup in the C₁₋₄ alkyl cycloalkyl may be a heterobicycloalkyl or aheterospiroalkyl group. More specifically, R₄ may be C₁₋₈alkyl(difluoroaryl), C₁₋₄ alkyl difluorocycloalkyl, C₁₋₈ alkyl difluoroheteroaryl, C₁₋₄ alkyl difluoroheterocycloalkyl, C₂₋₈ alkenyl(difluoroaryl), or C₂₋₈ alkenyl(difluoro heteroaryl).

The disclosure also provides the compound of any of par. [0008]-[0014],wherein R₅ is heteroaryl. In particular, R₅ may be oxadiazole, oxazole,n-methyl thiazole, tetrazole, thiazole, or triazole.

Pharmaceutical compositions are also provided comprising at least onepharmaceutically acceptable excipient and a therapeutically effectiveamount of the compound of any of par. [0008]-[0014]. The therapeuticallyeffective amount may be an amount effective for lowering blood pressure.Alternatively, the therapeutically effective amount is an amounteffective for the treatment of asthma, cardiomyopathy, diabetes,dyslipidemia, hypertension, inflammation, liver disease, metabolicdisorder, neurodegenerative disease, obesity, preeclampsia, or renaldysfunction.

In another embodiment, the disclosure provides the use in a treatment ofan apelin receptor (APJ) related disorder of a compound Formula I:

or a pharmaceutically acceptable salt, a prodrug, or a salt of aprodrug, wherein R₁ is represented by the formula:

wherein

is a monocyclic aryl or heteroaryl group; each A is independently C₁₋₈alkyl, C₁₋₈ alkyl(aryl), C₁₋₈ alkoxy, C₁₋₈ alkoxy aryl, C₂₋₈ alkenyl,C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, —CF₃, —(CH₂)_(x)NR₇R₈, —CN, —CONR₇R₈,—COR₇, —CO₂(CH₂)_(x)NR₇R₈, —CO₂R₇, halogen, hydroxyl, —N₃, —NHCOR₇,—NHSO₂C₁₋₈ alkyl, —NHCO₂C₁₋₈alkyl, —NO₂, —NR₇R₈, —O(CH₂)_(x)NR₇R₈,—O(CH₂)_(x)CO₂R₇, —OCOC₁₋₈alkyl, —OCO(CH₂)_(x)NR₇R₈, —SF₅, —SO₂NR₇R₈,—SO₍₁₋₃₎R₇, —SR₇, or tetrazolone; R₇ and R₈ are independently C₁₋₈alkoxy, aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈alkyl amido, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyltetrazol-5-one, C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkylthioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈cycloalkyl, —(CH₂)_(x)CONHR₉, —(CH₂)_(x)COR₉, —(CH₂)_(x)CO₂R₉, H, orheteroaryl; or R₇ and R₈ together make a 3-9 member ring which maycontain one or more heteroatoms; or R₇ and R₈ together make a 5-8nitrogen containing member ring with one or more carbonyl groups; n is1, 2, 3, 4or 5;

-   R₂ is C₃₋₈ alkyl, C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₃₋₈ cycloalkyl,    heteroaryl, or substituted aryl;-   R₄, R₅ and R₆ are independently adamantanyl, aryl, C₁₋₈ alkyl, C₁₋₈    alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₂₋₈ alkyl(aryl),    C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl)-CO₂R₇,    C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl    tetrazol-5-one, C₂₋₄ alkyl heterocycloalkyl, C₁₋₈ alkyl thioether,    C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl), C₂₋₈    alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈    cycloalkyl-CO₂R₇, —(CH₂)_(x)NR₇R₈, —(CH₂)_(x)OR₇, —(CH₂)_(x)NR₉COR₇,    —(CH₂)_(x)NR₉SO₂R₇, —(CH₂)_(x)N R₉CO₂R₇, —(CH₂)_(x)NHCOR₇,    —(CH₂)_(x)NHSO₂R₇, —(CH₂)_(x)NHCO₂R₇, —(CH₂)_(x)CONR₇R₈,    —(CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉, —(CH₂)_(x)CONR₇(CH₂)_(y)CONR₇R₈,    —(CH₂)_(x)CONR₇(CH₂)_(y)R₉, —(CH₂)_(x)COR₇, —(CH₂)_(x)CO₂R₇,    —(CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉, —CHR₇COR₉, —CHR₇CONHCHR₈COR₉ —CONR₇R₈,    —CONR₇(CH₂)_(x)CO₂R₈, —CONR₇CHR₈CO₂R₉, —CO₂R₉, H, or —NHCO₂R₇,    —(CH₂)_(x)SO₂NR₇R_(8;) —SF₅; or R₄ and R₅ together make a 4-8 member    ring which may be substituted with one or more heteroatoms; or R₄    and R₅ together make a 5-8 nitrogen containing member ring with one    or more carbonyl groups;-   wherein the group R₄ is substituted with one or more fluorine atoms;-   R₉ is aryl, C₁₋₈ alkoxy, C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₃₋₈    cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8;    and each y is independently 1-8.

In yet another embodiment, the disclosure provides the use in atreatment of an apelin receptor (APJ) related disorder of a compoundrepresented by the Formula II:

or a pharmaceutically acceptable salt, a prodrug, or a salt of aprodrug,

wherein R₁ is represented by the formula:wherein

is a monocyclic heteroaryl group;

-   each A is independently C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₁₋₈ alkoxy,    C₁₋₈ alkoxy aryl, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, —CF₃,    —(CH₂)_(x)NR₇R₈, —CN, —CONR₇R₈, —COR₇, —CO₂(CH₂)_(x)NR₇R₈, —CO₂R₇,    halogen, hydroxyl, —N₃, —NHCOR₇, —NHSO₂C₁₋₈alkyl, —NHCO₂C₁₋₈ alkyl,    —NO₂, —NR₇R₈, —O(CH₂)_(x)NR₇R₈, —O(CH₂)_(x)CO₂R₇, —OCOC₁₋₈ alkyl,    —OCO(CH₂)_(x)NR₇R₈, —SF₅, —SO₂NR₇R₈, —SO₍₁₋₃₎R₇, or —SR_(S); each R₇    and R₈ are independently C₁₋₈ alkoxy, aryl, C₁₋₈ alkyl, C₁₋₈ alkyl    alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₁₋₈ alkyl(aryl), C₁₋₈    alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl    heteroaryl, C₁₋₈ alkyl thioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl,    C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, —(CH₂)_(x)CONHR₉, —(CH₂)_(x)COR₉,    —(CH₂)_(x)CO₂R₉, H, or heteroaryl; or R₇ and R₈ together make a 3-9    member cycloalkyl or heterocycloalkyl group; n is 1, 2, 3, 4 or 5;    each x is independently 0-8;-   R₂ is present or absent, and if present, is C₃₋₈ alkyl, C₁₋₈ alkyl    (C₃₋₈ cycloalkyl), C₃₋₈ cycloalkyl, heteroaryl, or substituted aryl;-   R₃ is present or absent, is absent if R₂ is present, and if present    is C₁₋₈ alkyl, C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₃₋₈ cycloalkyl or    substituted aryl;-   R₄, R₅, and R₆ are independently adamantanyl, aryl, C₁₋₈ alkyl, C₁₋₈    alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₂₋₈ alkyl(aryl),    C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl)-CO₂R₇,    C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl    tetrazol-5-one, C₂₋₄ alkyl C₆ heterocycloalkyl, C₁₋₈ alkyl    thioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl), C₂₋₈    alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₉ cycloalkyl, C₃₋₈    cycloalkyl-CO₂R₇, —(CH₂)_(x)NR₇R₈, —(CH₂)_(x)OR₇, —(CH₂)_(x)NHCOR₇,    —(CH₂)_(x)NHSO₂R₇, —(CH₂)_(x)NHCO₂R₇, —(CH₂)_(x)CONR₇R₈,    —(CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉, —(CH₂)_(x)CONR₇(CH₂)_(y)CONR₈R₉,    —(CH₂)_(x)CONR₇(CH₂)_(y)R₉, —(CH₂)_(x)CONR₇(CH₂)_(y)SO₂R₉,    —(CH₂)_(x)COR₇, —(CH₂)_(x)CO₂R₇,    —(CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉,—CHR₇COR₉ —CHR₇CONHCHR₈COR₉ , —CONR₇R₈,    —CONR₇(CH₂)_(x)CO₂R₈, —CONR₇CHR₈CO₂R₉, —CO₂R₉, H, —NHCO₂R₇, —SF₅,    —SO₂NR₇R₈, or R₄ and R₅ together make a 4-9 member cycloalkyl or    heterocycloalkyl group;-   wherein the group R₄ is substituted with one or more fluorine atoms;-   R₉ is aryl, C₁₋₈ alkoxy, C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₃₋₈    cycloalkyl, H, heteroaryl, or hydroxyl; and each y is independently    1-8.

The use in a treatment of an apelin receptor (APJ) related disorder of acompound represented by the represented by Formula III

wherein n is 1, 2 or 3; each A is independently C₁-C₅ alkoxy, C₁-C₅alkyl, C₃₋₈ cycloalkyl, halogen, or —SF₅;

-   R₂ is C₃-C₆ alkyl, C₁₋₃ alkyl (C₃₋₆ cycloalkyl) or C₃-C₇ cycloalkyl;-   R₄ is aryl, C₁₋₄ alkyl, C₂₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈    cycloalkyl), C₁₋₈ alkyl heteroaryl, C₂₋₄ alkyl C₆ heterocycloalkyl,    C₂₋₈ alkenyl(aryl), C₂₋₈ alkenyl(heteroaryl), or heteroaryl;-   wherein the group R₄ is substituted with one or more fluorine atoms;    and-   R₁₀ is aryl, C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈    cycloalkyl), C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl tetrazol-5-one, C₃₋₈    cycloalkyl, or heteroaryl.

In another embodiment, the disclosure provides the use of any of par.[0017]-[0019], wherein the apelin receptor (APJ) related disorder isasthma, cardiomyopathy, diabetes, dyslipidemia, hypertension,inflammation, liver disease, metabolic disorder, neurodegenerativedisease, obesity, preeclampsia, or renal dysfunction.

In one embodiment, the disclosure provides the use of par. [0020],further comprising an α-blocker, an angiotensin converting enzyme (ACE)inhibitor, an angiotensin-receptor blocker (ARB), a β-blocker, a calciumchannel blocker, or a diuretic for the treatment of the apelin receptor(APJ) related disorder.

In another embodiment, the disclosure provides a compound represented bythe Formula IV:

or a pharmaceutically acceptable salt, a prodrug, or a salt of aprodrug, wherein R₁ is represented by the formula:

wherein

is a monocyclic heteroaryl group; each A is independently C₁₋₈ alkyl,C₁₋₈ alkyl(aryl), C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, —CF₃,—(CH₂)_(x)NR₇R₈, —CN, —CONR₇R₈, —COR₇, —CO₂(CH₂)_(x)NR₇R₈, —CO₂R₇,halogen, hydroxyl, —N₃, —NHCOR₇, —NHSO₂C₁₋₈ alkyl, —NHCO₂C₁₋₈ alkyl,—NO₂, —NR₇R₈, —O(CH₂)_(x)NR₇R₈, —O(CH₂)_(x)CO₂R₇, —OCOC₁₋₈ alkyl,—OCO(CH₂)_(x)NR₇R₈, —SF5, —SO₂NR₇R₈, —SO₍₁₋₃₎R₇, —SR₇, or tetrazalone;R₇ and R₈ are independently alkoxy, aryl, C₁₋₈ alkyl, C₁₋₈ alkylalcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₁₋₈ alkyl(aryl), C₁₋₈alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl,C₁₋₈ alkyl imidazolyl, C₁₋₈ alkyl indolyl, C₁₋₈ alkyl thioether, C₁₋₈alkyl thiol, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈ cycloalkyl,—(CH₂)_(x)CONHR₉, —(CH₂)_(x)COR₉, —(CH₂)_(x)CO₂R₉, H, or heteroaryl; orR₇ and R₈ together make a 3-8 member ring which may be substituted withone or more heteroatoms;

-   n is 1, 2, 3, 4 or 5;-   each x is independently 0-8;-   R₂ is present or absent, and if present, is C₃₋₈ alkyl, C₁₋₈ alkyl    (C₃₋₈ cycloalkyl), C₂₋₈ alkyl(aryl), C₃₋₈ cycloalkyl, heteroaryl, or    substituted aryl;-   R₃ is present or absent, is absent if R₂ is present, and if present    is C₁₋₈ alkyl, C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₂₋₈ alkyl(aryl), C₃₋₈    cycloalkyl or substituted aryl; provided that if n is two, both A's    are not chlorine;-   R₄, R₅, and R₆ are independently adamantanyl, aryl, C₁₋₈ alkyl, C₁₋₈    alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₁₋₈ alkyl(aryl),    C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl)-CO₂R₇,    C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkyl imidazolyl,    C₁₋₈ alkyl indolyl, C₁₋₈ alkyl tetrazol-5-one, C₁₋₈ alkyl thioether,    C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl), C₂₋₈    alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈    cycloalkyl-CO₂R₇, —(CH₂)_(x)NR₇R₈, —(CH₂)_(x)OR₇, —(CH₂)_(x)NHCOR₇,    —(CH₂)_(x)NHSO₂R₇, —(CH₂)_(x)NHCO₂R₇, —(CH₂)_(x)CONR₇R₈,    —(CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉, —(CH₂)_(x)CONR₇(CH₂)_(y)CONR₇R₈,    —(CH₂)_(x)CONR₇(CH₂)_(y)R₉, —(CH₂)_(x)COR₇, —(CH₂)_(x)CO₂R₇,    —(CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉, —CHR₇COR₉, —CHR₇CONHCHR₈COR₉, —CONR₇R₈,    —CONR₇(CH₂)_(x)CO₂R₈, —CONR₇CHR₈CO₂R₉, —CO₂R₉, H, or —NHCO₂R₇, —SF₅,    —SO₂NR₇R_(8;) or R₄ and R₅ together make a 4-8 member ring which may    be substituted with one or more heteroatoms; R₉ is aryl, C₁₋₈    alkoxy, C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₃₋₈ cycloalkyl, H,    heteroaryl, or hydroxyl;-   each y is independently 1-8;-   and Z is H₂ or ═0.

The composition of par. [0022] Formula IV may incorporate themodifications as described in par. [0011]-[0015] for Formulas I-III. Inaddition, compounds of Formula IV may be prepared in pharmaceuticalcompositions as described in par. [0016]. Moreover, disclosure providesthe use in a treatment of apelin receptor (APJ) related disorders, asdisclosed herein, of a compound represented by the Formula IV.

In a preferred embodiment of the compositions or uses of any of par.[0008]-[0023],

is phenyl or 2- or 3-pyridyl, n is 1, group A is in the ortho positionand is —CF₃, —CF₂CH₃, —CH₂CH₃, Cl, -cC₃H₅, —OCF₂H or —OCF₃.Alternatively, n is 2 and A₁ is —OCH₃ and A₂ is —OCH₃ or F. Morespecifically,

is

In another preferred embodiment of the compositions or uses of any ofpar. [0008]-[0023], R₂ is —CH₂cC₃H₅, —C(CH₃)₂cC₃H₅, -cC₄H₇,-cC₄H₆(CH₃)₂, —CH₂cC₄H₇, -cC₅H₉, -cC₅H₈F, -cC₅H₈(CH₃), -cC₅H₇(CH₃)₂,—CH₂cC₅H₉, —CH₂cC₅H₉, —cC₆H₁₁, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, or—C(CH₃)CH(CH₃)₂. In particular, R₂ may be

In another preferred embodiment of the compositions or uses of any ofpar. [0008]-[0024], R₄ may be

In an additional preferred embodiment, R₄ may be

If there are no fluorines in the group, the backbones of the R₄ groupsin par. [0026]-[0027] may be modified to contain one or more fluorineatoms by the replacement of one or more hydrogens. Alternatively, if theR₄ groups in par. [0026]-[0027] contain fluorines, the backbone may bemodified to incorporate additional fluorine substituents by replacementof aliphatic or aromatic hydrogens.

In yet another preferred embodiment, R₅ or R₁₀ may be

In preferred embodiments, two groups in the set of R₁, R₂, R₄, R₅ andR₁₀ are selected from the groups shown in par. [0024]-[0029]. In otherpreferred embodiments, three groups in the set of R₁, R₂, R₄, R₅ and R₁₀are selected from the groups in par. [0024]-[0029]. In yet anotherembodiment, four groups in the set of R₁, R₂, R₄, R₅ and R₁₀ areselected from the groups in par. [0024]-[0029].

For the compounds and uses above, the disclosure also includesbioisosteres such as tetrazolones and pentafluorosulfanyl. Inparticular, —CF₃, —CH₃, —O—CH₃, or —O—CF₃ or an aryl —CF₃, —CH₃, —O—CH₃,or —O—CF₃ may be replaced with —SF₅ or aryl-SF₅, respectively. SeeAlvarez et al. 2015 ACS Med Chem Let 6 1225-1230. Alternatively, a —CO₂Hmay be replaced with a tetrazolone. See Duncton et al. 2016 Org BiomolChem 14 9338-9342.

4. DETAILED DESCRIPTION OF THE DISCLOSURE

4.1. Definitions

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl group having at least one carbon-carbon double bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkene. The group may be in either the Z- and E-forms (or cis or transconformation) about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and thelike. The alkenyl group may be substituted or unsubstituted. In certainembodiments, an alkenyl group has from 2 to 20 carbon atoms and in otherembodiments from 2 to 8 carbon atoms.

“Alkoxy” refers to a radical —OR where R represents an alkyl,cycloalkyl, aryl, or heteroaryl group as defined herein. Representativeexamples include, but are not limited to, methoxy, ethoxy, propoxy,butoxy, cyclohexyloxy, and the like. The alkoxy group may be substitutedor unsubstituted.

“Alkyl” refers to a saturated, branched or straight-chain monovalenthydrocarbon group derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkyl groups include, butare not limited to, methyl, ethyl, propyls such as propan-1-yl,propan-2-yl, and cyclopropan-1-yl, butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl- propan-2-yl,cyclobutan-1-yl, tert-butyl, and the like. The alkyl group may besubstituted or unsubstituted; for example with methyl or a halogen(s)such as difluoro or trifluoro. In certain embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms. Alternatively, an alkyl group maycomprise from 1 to 8 carbon atoms.

“Alkyl(aryl)” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical alkyl(aryl) groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. In certain embodiments, an alkyl(aryl) group can be (C₆₋₂₀)alkyl(aryl) e.g., the alkyl group may be (C₁₋₁₀) and the aryl moiety maybe (C₅₋₁₀). The alkyl(aryl) group may be substituted or unsubstituted.

“Alkynyl” refers to an unsaturated branched or straight-chain having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl, propynyl,butenyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. Thealkynyl group may be substituted or unsubstituted. In certainembodiments, an alkynyl group has from 3 to 20 carbon atoms and in otherembodiments from 3 to 8 carbon atoms.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl encompasses 5- and 6-membered carbocyclicaromatic rings, for example, benzene or cyclopentadiene; bicyclic ringsystems wherein at least one ring is carbocyclic and aromatic, forexample, naphthalene, indane; or two aromatic ring systems, for examplebenzyl phenyl, biphenyl, diphenylethane, diphenylmethane. The aryl groupmay be substituted or unsubstituted, for example with a halogen, such asfluorine.

“Cycloalkyl” refers to a saturated or unsaturated cyclic alkyl group.Where a specific level of saturation is intended, the nomenclature“cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. The cycloalkylgroup may be substituted or unsubstituted. In certain embodiments, thecycloalkyl group can be C₃₋₁₀ cycloalkyl, such as, for example, C₆cycloalkyl or cC₆H_(12.) The cycloalkyl group may also be a bridgedbicyclic cycloalkyl group, a fused cycloalkyl group or a spirocycloalkyl group. Non-limiting examples of bridged bicyclic cycloalkylgroups are bicyclo[2.2.1]heptane, bicyclo[2.2.1]hexane,bicycle[2.2.2]octane. An example of a fused cycloalkyl group isbicyclo[4.4.0]decane or decalin. Non-limiting examples of spirocycloalkyl groups are spiro [3.3] heptane, spiro [4.3] octane, or spiro[5.4] decane.

“Disease” refers to any disease, disorder, condition, symptom, orindication.

“Halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Heteroaryl encompasses: 5- to 7-memberedaromatic, monocyclic rings containing one or more, for example, from 1to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N,O, and S, with the remaining ring atoms being carbon; and polycyclicheterocycloalkyl rings containing one or more, for example, from 1 to 4,or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O,and S, with the remaining ring atoms being carbon and wherein at leastone heteroatom is present in an aromatic ring. The heteroaryl group maybe substituted or unsubstituted.

For example, heteroaryl includes a 5- to 7-membered heteroaromatic ringfused to a 5- to 7-membered cycloalkyl ring and a 5- to 7-memberedheteroaromatic ring fused to a 5- to 7-membered heterocycloalkyl ring.For such fused, bicyclic heteroaryl ring systems wherein only one of therings contains one or more heteroatoms, the point of attachment may beat the heteroaromatic ring or the cycloalkyl ring. When the total numberof S and O atoms in the heteroaryl group exceeds 1, those heteroatomsare not adjacent to one another. In certain embodiments, the totalnumber of S and O atoms in the heteroaryl group is not more than 2. Incertain embodiments, the total number of S and O atoms in the aromaticheterocycle is not more than 1. Typical heteroaryl groups include, butare not limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, piperidine, pteridine, purine, pyran, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Incertain embodiments, the heteroaryl group can be between 5 to 20membered heteroaryl, such as, for example, a 5 to 10 memberedheteroaryl. In certain embodiments, heteroaryl groups can be thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole, and pyrazine.

“Heterocycloalkyl” refers to a non-aromatic monocyclic ring or fusednon-aromatic polycyclic rings with one or more heteroatom(s)independently selected from N, S and O, with the remaining ring atomsbeing carbon and wherein at least one heteroatom is present in eachnon-aromatic ring. The heterocycle group may be a three-member ring, afour member ring, a five member ring, a six member ring or a sevenmember ring. In certain embodiments, the heterocycloalkyl group is1,4-dioxane, 1,3-dioxolane, 1,4-dithiane, imidazolidine, morpholine,piperidine, piperidone, piperazine, pyrolidone, pyrrolidine, or1,3,5-trithiane. It may contain an imide. The heterocycloalkyl group maybe bicyclic such as an heterospiro group, e.g., heterospiro [3.3]heptanyl, heterospiro [3.4] octanyl, or heterospiro [5.5] undecanyls.The heterocycloalkyl group may be substituted or unsubstituted. Thus,heterocycloalkyl group encompasses heterocycloalkyl groups substitutedwith one or more halogens, such as 3,3-difluoropiperidine, or4,4-difluoropiperidine. In addition, the heterocycloalkyl group may besubstituted with a C₁-C₄ alkyl or C₁-C₄ halo alkyl group such as a —CF₃group.

“Pharmaceutically acceptable” refers to generally recognized for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, and the like; or (2) salts formed when an acidicproton present in the parent compound either is replaced by a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient,” “pharmaceutically acceptablecarrier,” or “pharmaceutically acceptable adjuvant” refer, respectively,to an excipient, carrier or adjuvant with which at least one compound ofthe present disclosure is administered. “Pharmaceutically acceptablevehicle” refers to any of a diluent, adjuvant, excipient or carrier withwhich at least one compound of the present disclosure is administered.

“Prodrug” refers to a precursor or derivative form of a pharmaceuticallyactive substance that is less bioactive compared to the parent drug andis capable of being enzymatically activated or converted into the moreactive parent form. Prodrug forms of the compounds described herein maydesigned to improve bioavailability or stability or reduce toxicity. Forexample, compounds of the invention having free amino, amido,carboxylic, hydroxyl, or thiol groups can be converted into prodrugs.See Rautio et al., 2008 Nat Rev Drug Dis 7 255-270. For instance, freecarboxyl groups can be derivatized as amides, carbamates, esters, orN-Mannich bases. Free hydroxy groups may be derivatized using groupsincluding but not limited to carbonates, dimethylaminoacetates, ethers,hemisuccinates, phosphate esters, and phosphoryloxymethyloxycarbonyls,as outlined in Fleisher et al., 1996 Advanced Drug Delivery Reviews 19,115-130. Carbamate prodrugs of hydroxy and amino groups are alsoincluded, as are carbonate prodrugs, sulfonate esters and sulfate estersof hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyland (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester,optionally substituted with groups including but not limited to ether,amine and carboxylic acid functionalities, or where the acyl group is anamino acid ester as described above, are also encompassed. Prodrugs ofthis type are described in Robinson et al., 1996 J Med Chem 39 10-18.Free amines can also be derivatized as amides, carbamates, imines,N-Mannich bases, oximes, phosphonamides, or sulfonamides. Carbonyls maybe derivatized to imine or oxime prodrugs. Thiols may be derivatized asesters or ethers. Prodrugs may also include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe invention. The amino acid residues include but are not limited tothe 20 naturally occurring amino acids commonly designated by threeletter symbols and also includes beta-alanine, citrulline, demosine,gamma-aminobutyric acid, homocysteine, homoserine, 4-hydroxyproline,hydroxylysine, isodemo sine, 3-methylhistidine, norvalin, methioninesulfone, and ornithine.

“Stereoisomer” refers to an isomer that differs in the arrangement ofthe constituent atoms in space. Stereoisomers that are mirror images ofeach other and optically active are termed “enantiomers,” andstereoisomers that are not mirror images of one another and areoptically active are termed “diastereoisomers.”

“Subject” includes mammals and humans. The terms “human” and “subject”are used interchangeably herein.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, CO₂H, cyano,difluoro, difluoromethyl, halogen, hydroxyl, keto, methyl, —N₃, —NH₂,—SO₍₁₋₃₎H, —SH, or trifluoromethyl.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease or disorder, is sufficient toaffect such treatment for the disease, disorder, or symptom. The“therapeutically effective amount” can vary depending on the compound,the disease, disorder, and/or symptoms of the disease or disorder,severity of the disease, disorder, and/or symptoms of the disease ordisorder, the age of the subject to be treated, and/or the weight of thesubject to be treated. An appropriate amount in any given instance canbe readily apparent to those skilled in the art or capable ofdetermination by routine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease, disorder, or at least one of the clinical symptoms of a diseaseor disorder, reducing the development of a disease, disorder or at leastone of the clinical symptoms of the disease or disorder, or reducing therisk of developing a disease or disorder or at least one of the clinicalsymptoms of a disease or disorder. “Treating” or “treatment” also refersto inhibiting the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, or inhibiting at leastone physical parameter which may not be discernible to the subject.Further, “treating” or “treatment” refers to delaying the onset of thedisease or disorder or at least symptoms thereof in a subject which maybe exposed to or predisposed to a disease or disorder even though thatsubject does not yet experience or display symptoms of the disease ordisorder.

Pairs of the functional groups defined herein may be combined in achemically rational way. For example, C₁-C₈ alkyl amino means thefunctional group C₁-C₈ alkyl, e.g., -nC₅H₁₁, is combined with thefunctional group, amino, e.g., —NH₂ to form in this example-nC₅H₁₀NH_(2.) Likewise, C₁-C₈ alkyl alcohol would mean a group, e.g.,nC₃H₆OH. Similarly, C₁-C₈ alkoxy aryl means the functional group C₁-C₈alkoxy, e.g., —CH₂CH₂OCH₂CH₃ or —OCH₂CH₃ combined with an aryl group,e.g., —C₆H₅F to form —CH₂CH₂OCH₂CH₂-C₆H₅F or —OCH₂CH₃—C₆H₅F,respectively.

As used herein the substituents R₄, R₅, R_(6,) R₇, or R₈ mayindependently may be single α, β, γ, δ amino acids, or theircorresponding side chains, such as the twenty naturally occurring aminoacids, e.g., alanine (Ala/A); arginine (Arg/R); asparagine (Asn/N);aspartic acid (Asp/D); cysteine (Cys/C); glutamic acid (Glu/E);glutamine (Gln/Q); glycine (Gly/G); histidine (His/H); isoleucine(Ile/I); leucine (Leu/L); lysine (Lys/K); methionine (Met/M);phenylalanine (Phe/F); proline (Pro/P); Serine (Ser/S); threonine(Thr/T); tryptophan (Trp/W); tyrosine (Tyr/Y); and valine (Val/V). Theindividual amino acids may of either the R or the S chirality.Alternatively, R₄, R₅, R_(6,) R₇, or R₈ independently may be two orthree amino acids linked by a peptide bond. R₄, R₅, R_(6,) R₇, or R₈independently may be dipeptides or tripeptides (Hobbs et al., Proc NatAcad Sci USA. 1993, 90, 6909-6913); U.S. Pat. No. 6,075,121 (Bartlett etal.) peptoids; or vinylogous polypeptides (Hagihara et al., J Amer ChemSoc. 1992, 114, 6568), the contents of which are hereby incorporated byreference in their entireties. R₄, R₅, R_(6,) R₇, or R₈ independentlymay be part of the extended unnatural amino acids, e.g., Xie andSchultz, Nat Rev Mol Cell Biol. 2006, 7(10):775-82 or Wang et al., ChemBiol. 2009, 16(3):323-36, the contents of which are hereby incorporatedby reference in their entireties.

4.2. Deuterated and Other Isotopic Variants

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I, and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Substitutionwith positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can beuseful in Positron Emission Topography (PET) studies.

Further, substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents. Inanother embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art.

Such isotope-labeled compounds can be conveniently prepared by carryingout the procedures disclosed in the Examples disclosed herein andSchemes by substituting a readily available isotope-labeled reagent fora non-labeled reagent. In some instances, compounds may be treated withisotope-labeled reagents to exchange a normal atom with its isotope, forexample, hydrogen for deuterium can be exchanged by the action of adeuteric acid such as D₂SO₄/D₂O. Alternatively, deuterium may be alsoincorporated into a compound using methods such as through reductionsuch as using LiAlD₄ or NaBD₃, catalytic hydrogenation or acidic orbasic isotopic exchange using appropriate deuterated reagents such asdeuterides, D₂ and D₂O. In addition to the above, PCT publications,WO2014/169280; WO2015/058067; U.S. Pat. Nos. 8,354,557; 8,704,001 and USPatent Application Publication Nos.; 2010/0331540; 2014/0081019;2014/0341994; 2015/0299166, the methods are hereby incorporated byreference.

4.3. Pharmaceutical Compositions

The disclosure also provides pharmaceutical compositions comprising aneffective amount of a compound Formula I (e.g., any of the formulaeand/or structures disclosed herein), or a pharmaceutically acceptablesalt of said compound; and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this disclosure include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. If required, the solubility andbioavailability of the compounds of the present disclosure inpharmaceutical compositions may be enhanced by methods well-known in theart. One method includes the use of lipid excipients in the formulation.See “Oral Lipid-Based Formulations: Enhancing the Bioavailability ofPoorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),”David J. Hauss, ed. Informa Healthcare, 2007; and “Role of LipidExcipients in Modifying Oral and Parenteral Drug Delivery: BasicPrinciples and Biological Examples,” Kishor M. Wasan, ed.Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this disclosure optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866 (Infeld et al.); and US Pat. Pubs. 20060094744 (Maryanoffet al.) and 20060079502 (Lang).

The pharmaceutical compositions of the disclosure include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),pulmonary, vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product. In certain embodiments, the compound is administeredorally. Compositions of the present disclosure suitable for oraladministration may be presented as discrete units such as capsules,sachets, or tablets each containing a predetermined amount of the activeingredient; a powder or granules; a solution or a suspension in anaqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion;a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.Soft gelatin capsules can be useful for containing such suspensions,which may beneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this disclosure may be administeredin the form of suppositories for rectal administration. Thesecompositions can be prepared by mixing a compound of this disclosurewith a suitable non-irritating excipient which is solid at roomtemperature but liquid at the rectal temperature and therefore will meltin the rectum to release the active components. Such materials include,but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this disclosure may be administeredby nasal aerosol or inhalation. Such compositions are prepared accordingto techniques well-known in the art of pharmaceutical formulation andmay be prepared as solutions in saline, employing benzyl alcohol orother suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art. See, e.g., U.S. Pat. No. 6,803,031 (Rabinowitz& Zaffaroni).

Topical administration of the pharmaceutical compositions of thisdisclosure is especially useful when the desired treatment involvesareas or organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this disclosure include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene or polyoxypropylene compounds, emulsifying wax, andwater. Alternatively, the pharmaceutical composition can be formulatedwith a suitable lotion or cream containing the active compound suspendedor dissolved in a carrier. Suitable carriers include, but are notlimited to, mineral oil, sorbitan monostearate, polysorbate 60, cetylesters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, andwater. The pharmaceutical compositions of this disclosure may also betopically applied to the lower intestinal tract by rectal suppositoryformulation or in a suitable enema formulation. Topically-transdermalpatches and iontophoretic administration are also included in thisdisclosure.

Application of the therapeutics may be local, so as to be administeredat the site of interest. Various techniques can be used for providingthe compositions at the site of interest, such as injection, use ofcatheters, trocars, projectiles, pluronic gels, stents, sustained drugrelease polymers or other devices which provide for internal access.Thus, according to yet another embodiment, the compounds of thisdisclosure may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. No. 6,099,562 (Ding & Helmus); U.S. Pat. No.5,886,026 (Hunter et al.); and U.S. Pat. No. 5,304,121 (Sahatjian). Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the disclosure provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the disclosure provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis disclosure. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the disclosure provides an implantablemedical device coated with a compound or a composition comprising acompound of this disclosure, such that said compound is therapeuticallyactive.

According to another embodiment, the disclosure provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this disclosure, such that saidcompound is released from said device and is therapeutically active.Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this disclosure, a composition of this disclosure may bepainted onto the organ, or a composition of this disclosure may beapplied in any other convenient way.

In one embodiment, this disclosure provides a composition comprising acompound of Formula I, or more specific compounds disclosed herein, totreat or prevent asthma, atherosclerosis, cancer, cardiomyopathy,diabetes, dyslipidemia, HIV neurodegeneration, hypertension,inflammation, liver disease, metabolic disorder, neurodegenerativedisease, obesity, or preeclampsia. In another embodiment, the disclosureprovides a composition comprising a compound of Formula I, or morespecific compounds disclosed herein, to treat or prevent cancer, cellproliferation, diabetes, fluid homeostasis, heart diseases (e.g.,hypertension and heart failure, such as congestive heart failure), HIVinfection, immune function, obesity, stem cell trafficking, metastaticcancer or a vein-related disorder such as an angioma, a venousinsufficiency, a stasis, or a thrombosis.

In another embodiment, a composition of this disclosure furthercomprises a second therapeutic agent. In one embodiment, the secondtherapeutic agent is one or more additional compounds of the disclosure.In another embodiment, the second therapeutic agent may be selected fromany compound or therapeutic agent known to have or that demonstratesadvantageous properties when administered with a compound having thesame mechanism of action as the APJ receptor compound of Formula I.

In a particular embodiment, the second therapeutic is an agent useful inthe treatment or prevention of a disease or condition selected fromacute decompensated heart failure (ADHF), amyotrophic lateral sclerosis,arrhythmia, asthma, atherosclerosis, atherosclerosis, atrialfibrillation, Brugada syndrome, burn injuries (including sunburn),cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents,chronic heart failure, diabetes (including gestational diabetes),dyslipidemia, HIV neurodegeneration, hypertension, inflammation,ischemic cardiovascular diseases, liver disease, metabolic disorder,neurodegenerative disease, obesity, peripheral arterial disease,preeclampsia, pulmonary hypertension, restenosis, transient ischemicattacks, traumatic brain injuries, ventricular tachycardia, or waterretention. In another embodiment, the second therapeutic is an agentuseful in the treatment or prevention of a disease or condition selectedfrom cancer, cell proliferation, diabetes, fluid homeostasis, heartdiseases (e.g., hypertension and heart failure, such as congestive heartfailure), HIV infection, immune function, obesity, stem celltrafficking, or metastatic cancer.

For example, when the disease or condition is congestive heart failure,the second therapeutic agent can be selected from: ACE inhibitors, betablockers, vasodilators, calcium channel blockers, loop diuretics,aldosterone antagonists, and angiotensin receptor blockers.

When the disease or condition being treated is hypertension, the secondtherapeutic agent can be selected from: α-blockers, β-blockers, calciumchannel blockers, diuretics, natriuretics, saluretics, centrally actingantihypertensives, angiotensin converting enzyme (ACE) inhibitors, dualACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptorblockers (ARBs), aldosterone synthase inhibitors, aldosterone-receptorantagonists, or endothelin receptor antagonists.

Non-limiting examples of α-Blockers include doxazosin, prazosin,tamsulosin, and terazosin.

Non-limiting examples of (β-Blockers for combination therapy areselected from acebutolol, acetutolol, atenolol, bisoprol, bupranolol,carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol,nadolol, oxprenolol, penbutolol, pindolol, propanolol, taliprolol, andtheir pharmaceutically acceptable salts.

Non-limiting examples of calcium channel blockers includedihydropyridines (DHPs) and non-DHPs. The preferred DHPs are selectedfrom the group consisting of amlodipine, felodipine, isradipine,lacidipine, nicardipine, nifedipine, nigulpidine, niludipine,nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, andtheir pharmaceutically acceptable salts. Non-DHPs are selected fromanipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil,prenylamine, tiapamil, and verampimil and their pharmaceuticallyacceptable salts.

Non-limiting examples of thiazide derivative include amiloride,chlorothalidon, chlorothiazide, hydrochlorothiazide, andmethylchlorothiazide.

Non-limiting examples of centrally acting antiphypertensives includeclonidine, guanabenz, guanfacine and methyldopa.

Non-limiting examples of ACE inhibitors include alacepril, benazepril,benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril,perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril,temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors arebenazepril, enalpril, lisinopril, and ramipril.

Non-limiting examples of dual ACE/NEP inhibitors are, for example,omapatrilat, fasidotril, and fasidotrilat.

Non-limiting examples of preferred ARBs include candesartan, eprosartan,irbesartan, losartan, olmesartan, tasosartan, telmisartan, andvalsartan.

Non-limiting examples of preferred aldosterone synthase inhibitors areanastrozole, fadrozole, and exemestane.

Non-limiting examples of preferred aldosterone-receptor antagonists arespironolactone and eplerenone.

Non-limiting examples of preferred endothelin antagonist include, forexample, bosentan, enrasentan, atrasentan, darusentan, sitaxentan, andtezosentan and their pharmaceutically acceptable salts.

In one embodiment, the disclosure provides separate dosage forms of acompound of this disclosure and one or more of any of theabove-described second therapeutic agents, wherein the compound andsecond therapeutic agent are associated with one another. The term“associated with one another” as used herein means that the separatedosage forms are packaged together or otherwise attached to one anothersuch that it is readily apparent that the separate dosage forms areintended to be sold and administered together (within less than 24 hoursof one another, consecutively or simultaneously).

In the pharmaceutical compositions of the disclosure, the compound ofthe present disclosure is present in an effective amount. As usedherein, the term “effective amount” refers to an amount which, whenadministered in a proper dosing regimen, is sufficient to treat(therapeutically or prophylactically) the target disorder. For example,and effective amount is sufficient to reduce or ameliorate the severity,duration or progression of the disorder being treated, prevent theadvancement of the disorder being treated, cause the regression of thedisorder being treated, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy. Preferably, the compound ispresent in the composition in an amount of from 0.1 to 50 wt. %, morepreferably from 1 to 30 wt. %, most preferably from 5 to 20 wt. %.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

The compounds for use in the method of the disclosure can be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for subjects undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form can be for a single daily treatment dose or one ofmultiple daily treatment doses (e.g., about 1 to 4 or more times perday). When multiple daily treatment doses are used, the unit dosage formcan be the same or different for each dose. 4.4. Methods of Treatment

The disclosure also includes methods of treating diseases, disorders orpathological conditions which benefit from modulation of the APJreceptor comprising administering an effective amount of an APJ receptorcompound of the disclosure to a subject in need thereof. Diseases andconditions which can benefit from modulation (inhibition or activation)of the APJ receptor include, but are not limited to, acute decompensatedheart failure (ADHF), amyotrophic lateral sclerosis, arrhythmia, asthma,atherosclerosis, atherosclerosis, atrial fibrillation, Brugada syndrome,burn injuries (including sunburn), cancer, cardiac fibrosis,cardiomyopathy, cerebrovascular accidents, chronic heart failure,diabetes (including gestational diabetes), dyslipidemia, HIVneurodegeneration, hypertension, inflammation, ischemic cardiovasculardiseases, liver disease, metabolic disorder, neurodegenerative disease,obesity, peripheral arterial disease, preeclampsia, pulmonaryhypertension, restenosis, transient ischemic attacks, traumatic braininjuries, ventricular tachycardia, or water retention. Morespecifically, the hypertension may be pulmonary arterial hypertension.The liver disease may be alcoholic liver disease, toxicant-induced liverdisease or viral-induced liver disease and the renal dysfunction may bepolycystic kidney disease. The apelin receptor system is involved invein-related disorders. See, e.g., Lathen et al., “ERG-APLNR AxisControls Pulmonary Venule Endothelial Proliferation in PulmonaryVeno-Occlusive Disease” 2014 Circulation 130: 1179-1191. Apelin receptorsystem has also been implicated in heart failure. See, e.g., Sheikh etal., “In vivo genetic profiling and cellular localization of apelinreveals a hypoxia-sensitive, endothelial-centered pathway activated inischemic heart failure” 2007 Am J Physiol Heart Circ Physiol294:H₈₈-H_(98.) The contents of both Lathen et al. and Sheikh et al. arehereby incorporated by reference in their entireties into the presentdisclosure.

In one non-limiting embodiment, the disclosure provides a method oftreating an apelin receptor (APJ) related disorder in a subject whichcomprises administering to the subject the compound of embodiment 1. Theapelin receptor (APJ) related disorder may be asthma, atherosclerosis,cancer, cardiomyopathy, diabetes, dyslipidemia, hypertension,inflammation, liver disease, metabolic disorder, neurodegenerativedisease, obesity, or preeclampsia. The disclosure provides methodsfurther comprising treating the subject with an α-blocker, anangiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptorblocker (ARB), a β-blocker, a calcium channel blocker, or a diuretic.Alternatively, the disclosure provides a method to treat or prevent avein-related disorder such as an angioma, a venous insufficiency, astasis or a thrombosis.

In addition, the disclosure provides a method of preventing HIVneurodegeneration in a subject which comprises administering to thesubject the compound of embodiment 1.

In one embodiment, an effective amount of a compound of this disclosurecan range from about 0.005 mg to about 5000 mg per treatment. In morespecific embodiments, the range is from about 0.05 mg to about 1000 mg,or from about 0.5 mg to about 500 mg, or from about 5 mg to about 50 mg.Treatment can be administered one or more times per day (for example,once per day, twice per day, three times per day, four times per day,five times per day, etc.). When multiple treatments are used, the amountcan be the same or different. It is understood that a treatment can beadministered every day, every other day, every 2 days, every 3 days,every 4 days, every 5 days, etc. For example, with every other dayadministration, a treatment dose can be initiated on Monday with a firstsubsequent treatment administered on Wednesday, a second subsequenttreatment administered on Friday, etc. Treatment is typicallyadministered from one to two times daily. Effective doses will alsovary, as recognized by those skilled in the art, depending on thediseases treated, the severity of the disease, the route ofadministration, the sex, age and general health condition of thesubject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician.

Alternatively, the effective amount of a compound of the disclosure isfrom about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 50mg/kg/day, or from about 1 mg/kg/day to 10 mg/kg/day.

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to said subject one or more secondtherapeutic agents. The choice of second therapeutic agent may be madefrom any second therapeutic agent known to be useful forco-administration with a compound that modulates the APJ receptor. Thechoice of second therapeutic agent is also dependent upon the particulardisease or condition to be treated. Examples of second therapeuticagents that may be employed in the methods of this disclosure are thoseset forth above for use in combination compositions comprising acompound of this disclosure and a second therapeutic agent.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisdisclosure as part of a single dosage form (such as a composition ofthis disclosure comprising a compound of the disclosure and a secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis disclosure. In such combination therapy treatment, both thecompounds of this disclosure and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this disclosure, comprising both a compound of thedisclosure and a second therapeutic agent, to a subject does notpreclude the separate administration of that same therapeutic agent, anyother second therapeutic agent or any compound of this disclosure tosaid subject at another time during a course of treatment.

In one embodiment of the disclosure, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisdisclosure is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this disclosure is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

4.5. Kits

The present disclosure also provides kits for use to treat the targetdisease, disorder or condition. These kits comprise (a) a pharmaceuticalcomposition comprising a compound of Formula I, or a salt thereof,wherein said pharmaceutical composition is in a container; and (b)instructions describing a method of using the pharmaceutical compositionto treat the target disease, disorder or condition.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,ampules, divided or multi-chambered holders bottles, wherein eachdivision or chamber comprises a single dose of said composition, adivided foil packet wherein each division comprises a single dose ofsaid composition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. In one embodiment, thecontainer is a blister pack.

The kits of this disclosure may also comprise a device to administer orto measure out a unit dose of the pharmaceutical composition. Such adevice may include an inhaler if said composition is an inhalablecomposition; a syringe and needle if said composition is an injectablecomposition; a syringe, spoon, pump, or a vessel with or without volumemarkings if said composition is an oral liquid composition; or any othermeasuring or delivery device appropriate to the dosage formulation ofthe composition present in the kit.

In certain embodiments, the kits of this disclosure may comprise in aseparate vessel of container a pharmaceutical composition comprising asecond therapeutic agent, such as one of those listed above for use forco-administration with a compound of this disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The article “a” and “an” areused herein to refer to one or more than one (i.e., to at least one) ofthe grammatical object(s) of the article. By way of example, “anelement” means one or more elements.

Throughout the specification the word “comprising,” or variations suchas “comprises” or “comprising,” will be understood to imply theinclusion of a stated element, integer or step, or group of elements,integers or steps, but not the exclusion of any other element, integeror step, or group of elements, integers or steps. The present disclosuremay suitably “comprise”, “consist of”, or “consist essentially of”, thesteps, elements, and/or reagents described in the claims.

It is further noted that the claims may be drafted to exclude anyoptional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely”,“only” and the like in connection with the recitation of claim elements,or the use of a “negative” limitation.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the disclosure. The upper and lower limits of these smallerranges may independently be included or excluded in the range, and eachrange where either, neither or both limits are included in the smallerranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

The following Examples further illustrate the disclosure and are notintended to limit the scope of the disclosure. In particular, it is tobe understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

5. EXAMPLES

5.1. Representative Compounds

TABLE 1 ID [M + H]+/ # STRUCTURE [M − H]− 253

587.3 296

533.7 297

464.8 298

522.7 299

516.8 300

450.8 301

498.9 302

505.7 303

557.9 304

570.9 305

543.9 306

578.4 307

499.7 308

512.3 309

485.4 310

522.6 311

464.8 312

555.0 313

567.5 314

540.3 315

504.7 316

541.7 317

485.1 318

538.6 319

569.8 320

567.6 321

519.8 322

513.7 323

511.5 324

566.5 325

564.6 326

565.8 327

568.7 328

552.9 329

580.8 330

527.7 331

566.4 332

583.1 333

555.0 334

570.9 335

588.5 336

557.1 337

580.7 338

582.0 339

565.4 340

579.9 341

553.8 342

716.4 343

537.6 344

604.4 345

568.4 346

582.5 347

526.4 348

588.6 349

564.6 350

566.5 351

595.6 352

497.6 353

688.5 354

546.4 355

572.4 356

580.5 357

554.5 358

484.6 359

576.4 360

538.4 361

522.5 362

498.4 363

520.5 364

523.6 365

492.5 366

608.4 367

570.4 368

494.5 369

511.5 370

556.5 371

520.5 372

540.5 373

594.5 374

509.4 375

493.5 376

481.2 377

495.2 378

499.4 379

580.7 380

574.7 381

557.9 382

588.5 383

573.6 384

617.4 385

428.6 386

442.2 387

559.2 388

574.2 389

478.3 390

517.0 391

473.6 392

491.4 393

456.4 394

509.3 395

545.2 396

560.1 397

534.5 398

538.4 399

538.5 400

556.5 401

476.8 402

560.6 403

502.0 404

539.1 405

539.1 406

549.7 407

526.5 408

560.5 409

585.7 410

585.6 411

556.9 412

557.0 413

532.4 414

522.4 415

561.2 416

563.1 417

592.3 418

544.1 419

543.9 420

545.8 421

566.1 422

523.1 423

543.2 424

543.9 425

596.9 426

625.7 427

609.0 428

621.0 429

591.0 430

625.9 431

639.0 432

539.4 433

509.0 434

566.4 435

544.1 436

639.7 437

566.4 438

516.9 439

632.7 440

638.9 441

541.5 442

485.4 443

588.4 445

536.9 447

605.8 448

539.9 449

478.3 450

532.6 451

623.4 452

588.9 457

563.5 458

545.7 459

599.9 460

597.9 463

518.0 464

532.0 465

522.7 466

563.5 467

508.5 468

508.5 469

563.4 470

541.5 471

556.1 475

610.0 479

598.2 480

582.9 481

571.9 482

585.8 483

588.4 484

506.5 485

527.8 486

508.5 487

573.7

489

671.7 490

573.9 491

561.9 492

575.8 493

561.9 494

595.8 495

605.8 496

628.6 497

570.7 498

585.8 499

491.7 500

600.5 501

557.6 502

614.6 503

571.7 504

546.7 505

573.7 506

559.6 507

573.4 508

521.3 509

557.2 510

585.9 511

588.0 514

574.3 515

610.4 516

519.2 517

588.3 518

513.6 519

528.0 520

595.8 521

586.2 522

603.1 523

568.6 524

582.9 526

464.2 527

438.1 528

424.1 529

672.5 533

519.8 534

515.2 535

568.2 536

588.2 537

525.2 538

535.2 539

576.2 540

592.3 541

646.3 542

557.3 544

521.1 545

520.3 546

573.4 547

574.9 548

529.2 549

574.3 550

590.6 551

567.3 552

529.2 553

559.2 554

559.8 555

575.8 556

577.6 557

529.2 558

535.2 559

523.2 560

533.1 561

588.4 562

576.3 563

515.2 565

531.2 566

613.7 567

541.7 568

545.3 570

559.3 571

543.2 572

641.8 573

596.8 574

565.5 575

556.0 756

556.1 577

478.3 578

561.4 579

543.2 580

517.2 581

530.1 582

527.8 583

525.7 584

523.7 585

509.7 587

521.3 588

507.4 589

511.3 590

509.7 591

553.7 592

539.3 593

519.8 594

525.7 595

537.6 596

557.3 597

557.2 598

525.5 599

537.4 600

537.5 601

537.4 602

567.7 603

539.5 604

535.3 605

539.3 606

569.8 607

553.3 608

535.3 609

523.7 610

541.3 611

545.4 612

557.3 613

537.3 614

537.5 615

573.7 618

577.5 621

496.7 622

510.6 623

470.6 624

551.6 625

565.7 626

526.0 627

571.7 628

565.4 629

527.8 630

553.7 631

528.0 634

555.9 635

555.9 636

608.9 637

579.8 638

579.8 639

541.5 640

542.7 641

568.5 643

519.6 646

442.6 647

538.7 648

524.8 649

498.9 655

559.3

5.2. Method and Preparation of Representative Compounds

Intermediates 1-cyclopentyl-5-phenyl-1H-pyrazole-3-carboxylic acids weresynthesized as described in Scheme 2. Ethyl1-cyclopentyl-5-hydroxy-1H-pyrazole-3-carboxylate was obtained byreacting cyclopentylhydrazine-TFA salt and sodium diethyl oxaloacetatein the presence of acetic acid. Treatment of ethyl1-cyclopentyl-5-hydroxy-1H-pyrazole-3-carboxylate with phosphorusoxybromide provided ethyl5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylatein 51% yield. Suzukicoupling of ethyl 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate withappropriate aryl boronic acids provided intermediates with diverse5-substituted pyrazole ester that were then subjected to basichydrolysis to afford carboxylic acid intermediates.

Ethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate: To a solution ofcyclopentyl hydrazine ditrifluoroacetic acid salt (85 g, 251 mmol) in500 mL EtOH was added AcOH (14.4 mL, 251 mmol). Sodium diethyloxaloacetate (48 g, 228 mmol) was added portionwise under stirring andthe resulting mixture was heated to reflux for 24 h. The reactionmixture was cooled to rt and the solvent was evaporated in vacuo. Theresidue was partitioned between EtOAc (500 mL) and 0.5 N HCl (750 mL)and the organic phase was separated. The aqueous phase was extractedwith EtOAc (200 mL×2) and the organic phases were combined, washed withbrine (300 mL), dried using Na₂SO₄ and concentrated to afford crude oil.Crude oil was diluted with 30 mL EtOAc and then MTBE (200 mL) was addedto afford a white crystalline precipitate which was filtered and driedto give 32.6 g of ethyl5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylateas white solid. TLCR_(f) =0.50 (hexane/EtOAc, 3:1); ¹H NMR (200 MHz, CDCl₃): δ=1.22-1.30(t, 3H, CH₃), 1.58-1.68 (m, 2H, CH₂), 1.82-2.10 (m, 6H, CH₂×3),4.22-4.32 (q, 2H, CH₂), 4.80-4.90 (m, 1H, CH), 6.90 (s, 1H, Ar). LCMS(ESI): m/z calculated for C₁₁H₁₆N₂O₃ [M+H⁺]: 225, Found: 225.2.

Ethyl 5-bromo-1-cylopentyl-1H-pyrazole-3-carboxylate: To a suspension ofethyl 5-hydroxy-1-cylopentyl-1H-pyrazole-3-carboxylate (32.6 g, 145mmol) in CH₃CN (360 mL) was added POBr₃ (209 g, 725 mmol) in portionsand the mixture was heated to reflux for 18 h. Reaction mixture wascooled to 0° C. and added slowly to sat. Na₂CO₃ (1000 mL) at 0° C. Theproduct was extracted using EtOAc (500 mL×3) and the organic phase wasdried using Na₂SO₄, silica gel (60 g) was added, and the solvent wereevaporated in vacuo to afford a silica plug. Purification was performedby flash chromatography using Combiflash® R_(f) (0-10% EtOAc in Hexanes)and the fractions containing the product (TLC) were pooled andevaporated to provide 21 g of ethyl5-bromo-1-cylopentyl-1H-pyrazole-3-carboxylateas a brown oil. TLC R_(f)=0.80 (hexane/EtOAc, 3:1); ¹H NMR (200 MHz, CDCl₃): δ=1.22-1.30 (t, 3H,CH₃), 1.58-1.68 (m, 2H, CH₂), 1.82-2.10 (m, 6H, CH₂×3), 4.22-4.32 (q,2H, CH₂), 4.80-4.90 (m, 1H, CH), 6.90 (s, 1H, Ar). LCMS (ESI): m/zcalculated for C₁₁H₁₅BrN₂O₂ [M⁺, Br⁷⁹]: 287, Found: 287.3; m/zcalculated for C₁₁H₁₅BrN₂O₂ [M⁺, Br⁸¹]: 289, Found: 289.2.

General procedure for the synthesis of ethyl1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylates: To a solution of ethyl5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (1 equiv.) in THF undernitrogen atmosphere was added Pd(PPh₃)₄ (2 or 5 mol %) and appropriatearyl boronic acid (1.2 or 2.0 equiv.) followed by 2 M Na₂CO₃ (3 equiv.).The mixture was heated to reflux until TLC/LCMS showed no furtherutilization of reactant 5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate.Reaction mixture was cooled to rt and then quenched with water (2 mL)and extracted with EtOAc (2 mL×2). Organic phases were combined, driedusing Na₂SO₄, silica gel (200 mg) was added, and the solvent wereevaporated in vacuo to afford a silica plug. Purification was performedby flash chromatography using Combiflash® R_(f) (0-10% EtOAc in Hexanes)and the fractions containing the product (TLC) were pooled andevaporated to provide ethyl1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylates.

EXAMPLES

Ethyl1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate:Using the general procedure described above, reaction between5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (200 mg, 0.70 mmol) and2-trifluoromethoxyphenyl boronic acid (172.2 mg, 0.84 mmol) in thepresence of Pd(PPh₃)₄ (16 mg, 0.014 mmol) and 2 M Na₂CO₃ (1.04 mL, 2.1mmol) in THF (5 mL) for 18 h provided 204 mg (80%) of ethyl1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylateas a colorless oil. TLC R_(f) =0.85 (hexane/EtOAc, 3:1); ¹H NMR (200MHz, CDCl₃): δ=1.30-1.40 (t, 3H, CH₃), 1.42-1.60 (m, 2H, CH₂), 1.80-2.25(m, 6H, CH₂×3), 4.20-4.45 (m, 3H, CH and CH₂), 6.85 (s, 1H, Ar),7.20-7.50 (m, 4H, Ar). LCMS (ESI): m/z calculated for C₁₈H₁₉F₃N₂O₃+H[M+H⁺]: 369, Found: 369.1.

Ethyl 1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate: Usingthe general procedure described above, reaction between5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (200 mg, 0.7 mmol) and2-ethylphenyl boronic acid (125.4 mg, 0.84 mmol) in the presence ofPd(PPh₃)₄ (16 mg, 0.014 mmol) and 2 M Na₂CO₃ (1.04 mL, 2.1 mmol) in THF(5 mL) for 18 h provided 180 mg (83%) of ethyl1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate as a colorlessoil. TLC R_(f) =0.76 (hexane/EtOAc, 3:1); ¹H NMR (200 MHz, CDCl₃):δ=1.00-1.15 (t, 3H, CH₃), 1.25-1.40 (t, 3H, CH₃), 1.40-1.60 (m, 2H,CH₂), 1.80-2.30 (m, 6H, CH₂×3), 2.40-2.55 (q, 2H, CH₂), 4.15-4.25 (m,1H, CH), 4.25-4.35 (q, 2H, CH₂), 6.60 (s, 1H, Ar), 7.05-7.40 (m, 4H,Ar).LCMS (ESI): m/z calculated for C₁₉H₂₄N₂O₂[M+H⁺]: 313, Found: 313.2.

Ethyl1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate:Using the general procedure described above, reaction between5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (150 mg, 0.52 mmol) and2-methoxy, 6-fluorophenyl boronic acid (178 mg, 1.04 mmol) in thepresence of Pd(PPh₃)₄ (21 mg, 0.026 mmol) and 2 M Na₂CO₃ (0.78 mL, 1.56mmol)in THF (5 mL) for 18 h provided 80 mg (46%) of ethyl1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylateas acolorless oil. TLC R_(f) =0.75 (hexane/EtOAc, 3:1); ¹H NMR (200 MHz,CDCl₃): δ=1.30-1.40 (t, 3H, CH₃), 1.40-1.60 (m, 2H, CH₂), 1.80-2.25 (m,6H, CH₂×3), 3.80 (s, 3H, CH₃), 4.20-4.40 (m, 3H, CH and CH₂), 6.70-6.85(m, 3H, Ar), 7.30-7.40 (m, 1H, Ar). LCMS (ESI): m/z calculated forC₁₈H₂₁FN₂O₃ [M+H⁺]: 333, Found: 333.4.

Ethyl 1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate: Usingthe general procedure described above, reaction between5-bromo-1-cyclopentyl-1H-pyrazole-3-carboxylate (150 mg, 0.52 mmol) andthiazol-4-yl boronic acid (135 mg, 1.04 mmol) in the presence ofPd(PPh₃)₄ (21 mg, 0.026 mmol) and 2 M Na₂CO₃(0.78 mL, 1.56 mmol) in THF(5 mL) for 24 h provided 15 mg (10%) of ethyl1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylateas a colorlessoil. TLC R_(f)=0.72 (hexane/EtOAc, 3:1); ¹H NMR (200 MHz, CDCl₃):δ=1.20-1.30 (t, 3H, CH₃), 1.80-2.25 (m, 8H, CH₂×4), 4.65-4.80 (m, 2H,CH₂), 5.20-5.40 (m, 1H, CH), 6.75 (s, 1H, Ar), 7.40 (s, 1H, Ar), 8.90(s, 1H, Ar).¹H NMR purity: 85-90%. LCMS (ESI): m/z calculated forC₁₄H₁₇N₃O₂S [M+H⁺]: 292, Found: 292.2.

General Procedure for the Synthesis of1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylic Acids

To a solution of appropriate ester ethyl1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylate (1 equiv.) in THF (1 mL),MeOH (2 mL) and H₂O (1 mL) was added LiOH.H₂O (5 equiv.) and stirred atrt for 18 h. Solvent was evaporated in vacuo and the reaction mixturewas acidified to pH=4.0 using 1 N HCl and extracted with EtOAc (3 mL×2).Organic phases were combined, washed with brine (3 mL), dried usingNa₂SO₄, and the solvent were evaporated in vacuo to provideintermediates 1-cylopentyl-5-aryl-1H-pyrazole-3-carboxylic acids.

1-Cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylicacid: Using the general procedure described above, reaction betweenethyl1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate(120 mg, 0.33 mmol) and LiOH.H₂O (68.4 mg, 1.65 mmol) provided103 mg(93%) of1-cyclopentyl-5-(2-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylicacid as a white solid. TLC R_(f) =0.45 (CHCl₃/MeOH, 10:1); ¹H NMR (200MHz, DMSO-d₆):δ=1.40-1.60 (m, 2H, CH₂), 1.70-2.00 (m, 6H, CH₂×3),4.25-4.40 (m, 1H, CH), 6.70 (s, 1H, Ar), 7.50-7.70 (m, 4H, Ar). LCMS(ESI): m/z calculated for C₁₆H₁₅F₃N₂O₃ [M+H⁺]: 341, Found: 341.1.

1-Cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylic acid: Using thegeneral procedure described above, reaction between ethyl1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylate(120 mg, 0.38mmol) and LiOH.H₂O (80.7 mg, 1.90 mmol) provided 109 mg (99%) of1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazole-3-carboxylic acid as a whitesolid. TLC R_(f) =0.50 (CHCl₃/MeOH, 10:1); ¹H NMR (200 MHz, DMSO-d6):8=0.95-1.05 (t, 3H, CH₃), 1.40-1.60 (m, 2H, CH₂), 1.65-1.95 (m, 6H,CH₂×3), 2.30-2.40 (q, 2H, CH₂), 4.15-4.30 (m, 1H, CH), 6.60 (s, 1H, Ar),7.15-7.45 (m, 4H, Ar). LCMS (ESI): m/z calculated for C₁₇H₂₀N₂O₂ [M+H⁺]:285, Found: 285.2.

1-Cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylicacid: Using the general procedure described above, reaction betweenethyl1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylate (80mg, 0.24 mmol) and LiOH.H₂O (50.5 mg, 1.20 mmol) provided 80 mg (93%pure, 99%) of1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazole-3-carboxylic acidas a white solid. TLC R_(f) =0.35 (CHCl₃/MeOH, 10:1); ¹H NMR (200 MHz,CDCl₃): δ=1.40-1.60 (m, 2H, CH₂), 1.80-2.25 (m, 6H, CH₂×3), 3.80 (s, 3H,CH₃), 4.25-4.40 (m, 1H, CH), 6.70-6.85 (m, 3H, Ar), 7.30-7.50 (m, 1H,Ar). LCMS (ESI): m/z calculated for C₁₆H₁₇FN₂O₃ [M+H⁺]: 305, Found:305.2.

1-Cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylic acid: Using thegeneral procedure described above, reaction between ethyl1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylate (15 mg, 0.05mmol) and LiOH.H₂O (10.8 mg, 0.25 mmol) provided 13 mg (96%) of1-cyclopentyl-5-(thiazol-4-yl)-1H-pyrazole-3-carboxylic acid as a whitesolid. TLC R_(f) =0.35 (CHCl₃/MeOH, 10:1); NMR, LCMS (ESI): m/zcalculated for C₁₂H₁₃N₃O₂S [M+H⁺]: 264, Found: 264.0.

(R)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pent-4-enoate:To a stirred solution of (S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-hydroxypentanoate(1.07 g, 22 mmol) and o-nitrophenylselenocyanate (1 g, 44 mmol) in THF(30 mL) at 0° C. was added tributylphosphine (1.1 mL, 44 mmol) undernitrogen atmosphere. The reaction mixture was stirred at rt for 3 h.Silica gel (4 g) was added and the solvent was removed under reducedpressure. Reaction mixture was purified using Combiflash® R_(f) (0-40%of EtOAc in hexanes) and the fractions containing the product (TLC) werepooled and evaporated to afford 1.38 g (93%) of o-nitrophenylselenidederivative as a reddish brown solid. TLC R_(f)=0.40 (hexanes/EtOAc,2:1); LCMS (ESI): m/z calculated for C₃₂H₄₀N₄O₇Se +H⁺[M+H⁺]: 673; Found:673.2.

To a stirred solution of o-nitrophenylselenide derivative (1.38 g, 20mmol) in THF (6 mL) and MeOH (40 mL) was added 0.8 M aq. NaIO4 solution(8 mL, 60 mmol) dropwise at 0° C. Reaction mixture was brought to rt andstirred for 4 h. Ether was added and the mixture was washed withsaturated NaHCO₃ solution, brine and dried over Na₂SO₄. Silica gel (3 g)was added and the solvent was removed under reduced pressure to afford asilica gel plug which was purified using Combiflash® R_(f) (0-5% ofEtOAc in hexanes). Fractions containing the product (TLC) were pooledand evaporated to provide 940 mg (97%) of (R)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pent-4-enoateasred semisolid. TLC R_(f)=0.50 (hexanes/EtOAc, 2:1); ¹H NMR (200 MHz,CDCl₃): δ=1.45 (s, 9H, CH₃×3), 1.50-1.60 (m, 2H, CH₂), 1.80-2.10 (m, 6H,CH₂×3), 2.60-2.70 (d, 2H, CH₂), 3.70 (s, 6H, CH₃×2), 4.20-4.35 (m, 1H,CH), 4.95-5.10 (m, 1H, CH), 5.15-5.20 (m, 1H, CH), 5.25-5.35 (m, 1H,CH), 5.85-6.05 (m, 1H, CH), 6.55-6.70 (m, 3H, Ar), 7.30-7.40 (t, 1H,Ar), 7.45-7.55 (d, 1H, NH). LCMS (ESI): m/z calculated for C₂₆H₃₇N₃O₅[M+H⁺]: 470; Found: 470.2.

(R,E)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate:To a solution of (R)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pent-4-enoate(185 mg, 0.40 mmol) in anhydrous DMF (4 mL) was added 4-flourophenylbromide (0.08 mL, 0.80 mmol) and degassed for 5 min. Under argonatmosphere, Pd(OAc)2 (8.5 mg, 0.04 mmol), P(o-tolyl)₃ (23.5 mg, 0.08mmol) and K₂CO₃ (204 mg, 1.60 mmol) were added and the reaction mixturewas stirred at 110° C. for 20 h. Reaction mixture was cooled to rt,diluted with H₂O (10 mL) and extracted with EtOAc (10 mL×2). Combinedorganic phases were washed with brine and dried over Na₂SO₄. Silica gel(300 mg) was added and the solvent was removed in vacuo to afford asilica gel plug which was purified using Combiflash® R_(f) (0-30% ofEtOAc in hexanes). Fractions containing the product (TLC) were pooledand evaporated to provide 160 mg (72%) of (R,E)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoateasred oil. TLC R_(f) =0.55 (hexanes/EtOAc, 2:1);¹H NMR (200 MHz, CDCl₃):δ=1.40 (s, 9H, CH₃×3), 1.50-1.60 (m, 2H, CH₂), 1.75-2.10 (m, 6H, CH₂×3),2.70-2.80 (d, 2H, CH₂), 2.80 (s, 1.2H, DMF “CH₃”), 2.90 (s, 1.2H, DMF“CH₃”), 3.70 (s, 6H, CH₃×2), 4.20-4.35 (m, 1H, CH), 5.10-5.20 (m, 1H,CH), 6.20-6.30 (m, 1H, CH), 6.55-6.70 (m, 4H, Ar and CH), 6.90-7.05 (m,2H, Ar), 7.30-7.40 (m, 3H, Ar), 7.45-7.55 (d, 1H, NH), 8.00 (s, 0.4H,DMF “CHO”). LCMS (ESI): m/z calculated for C₃₂H₃₈FN₃O₅+H⁺[M+H⁺]: 564;Found: 564.0.

(R,E)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoicacid: To a solution of (R,E)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate(40 mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.25 mL, 3.5 mmol) andstirred at rt for 2 h. Solvent was removed in vacuo and diluted withCHCl₃. Solvent was removed to provide 45 mg (99%) of(R,E)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoicacid as colorless oil. TLC R_(f) =0.25 (CHCl₃/MeOH, 10:1); LCMS (ESI):m/z calculated for C₂₈H₃₀FN₃O₅ [M+H⁺]: 508, Found: 508.0.

(R,E)-N-(5-(cyclobutylamino)-1-(4-fluorophenyl)-5-oxopent-1-en-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide:To a solution of(R,E)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoicacid (45 mg, 0.08 mmol) and cyclobutylamine (16 mg, 0.2 mmol) in ACN (1mL) was added anhydrous NEt₃ (0.12 mL, 0.8 mmol) followed by TBTU (64mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. Reactionmixture was diluted with EtOAc (3 mL), and washed with sat. NaHCO₃ (2mL). Organic phase was extracted, added silica gel (100 mg) and purifiedusing Combiflash® R_(f) (0-60% of EtOAc in hexanes) and the fractionscontaining the product (TLC) were pooled and evaporated to afford 35 mg(86%) of(R,E)-N-(5-(cyclobutylamino)-1-(4-fluorophenyl)-5-oxopent-1-en-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamideasa white sticky solid. TLC R_(f) =0.45 (hexanes/EtOAc, 2:1); ¹H NMR (200MHz, CDCl₃): δ=1.45-2.05 (m, 12H, CH₂×6), 2.20-2.40 (m, 2H, CH₂),2.70-2.85 (m, 2H, CH₂), 3.70 (s, 6H, CH₃×2), 4.20-4.45 (m, 3H, CH×3),5.00-5.10 (m, 1H, CH), 6.25-6.50 (m, 2H, CH and NH), 6.50-6.60 (m, 1H,Ar), 6.60-6.70 (m, 2H, Ar), 6.90-7.00 (m, 2H, Ar), 7.25-7.40 (m, 3H,Ar), 7.45-7.60 (d, 1H, NH). LCMS (ESI): m/z calculated forC₃₂H₃₇FN₄O₄[M+H⁺]: 561; Found: 561.2.

(S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoate:To a solution of(R,E)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pent-4-enoate(120 mg, 0.2 mmol) in EtOAc (5 mL) was added 10% Pd/C (23 mg, 0.02 mmol)and stirred at rt under hydrogen atmosphere (balloon) for 18 h. Reactionmixture was filtered over Celite®, washed with EtOAc (15 mL),concentrated, and dried to obtain 120 mg (99%) of (S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoateas colorless oil. TLC R_(f) =0.50 (hexanes/EtOAc, 2:1); LCMS (ESI): m/zcalculated for C₃₂H₄₀FN₃O₅ [M+H⁺]: 566, Found: 566.1.

(S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoicacid: To a solution of (S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoate(115 mg, 0.2 mmol) in DCM (3 mL) was added TFA (0.50 mL, 7 mmol) andstirred at rt for 2 h. Solvent was removed in vacuo and diluted withCHCl₃. Solvent was removed to provide 98 mg (95%) of(S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoicacid as colorless oil. TLC R_(f) =0.25 (CHCl₃/MeOH, 10:1); LCMS (ESI):m/z calculated for C₂₈H₃₂FN₃O₅ [M+H⁺]: 510, Found: 510.2.

(S)—N-(1-(cyclobutylamino)-5-(4-fluorophenyl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide:To a solution of(S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(4-fluorophenyl)pentanoicacid (50 mg, 0.1 mmol) and cyclobutylamine (16 mg, 0.2 mmol) in ACN (1mL) was added anhydrous Et₃N (0.12 mL, 0.8 mmol) followed by TBTU (64mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. Reactionmixture was diluted with EtOAc (3 mL), and washed with sat. NaHCO₃ (2mL). Organic phase was extracted, added silica gel (100 mg) and purifiedusing Combiflash® R_(f) (0-60% of EtOAc in hexanes) and the fractionscontaining the product (TLC) were pooled and evaporated to afford 30 mg(54%) of (S)—N-(1-(cyclobutylamino)-5-(4-fluorophenyl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamideasa white sticky solid. TLC R_(f) =0.25 (hexanes/EtOAc, 2:1); ¹H NMR (200MHz, CDCl₃): δ=1.45-2.10 (m, 14H, CH₂×7), 2.10-2.25 (m, 2H, CH₂),2.45-2.60 (m, 2H, CH₂), 2.60-2.80 (m, 2H, CH₂), 3.70 (s, 6H, CH₃×2),4.20-4.45 (m, 3H, CH×3), 6.50-6.70 (m, 4H, Ar and NH), 6.85-7.00 (m, 2H,Ar), 7.05-7.40 (m, 4H, Ar and NH). LCMS (ESI): m/z calculated forC₃₂H₃₉FN₄O₄ [M+H⁺]: 563; Found: 563.1.

(S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate:To a solution of1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid(0.31 g, 0.98 mmol) in DCM (6 ml) were added DMF (1 drop) and oxalylchloride (0.11 ml, 1.28 mmol). The solution was stirred at rt for 1 h,concentrated to dryness and dissolved in DCM (3 ml). The DCM solutionwas added dropwise to a solution of (S)-tert-butyl3-amino-5-(piperidin-1-yl)pentanoate(0.23 g, 0.90 mmol) and Et₃N (0.42ml, 2.7 mmol) in DCM (5 ml) at rt, and the mixture was stirred at rt for2 h. It was washed with NaHCO₃ (sat., 10 mL), dried (Na₂SO₄),concentrated, and purified using 0-3% MeOH in DCM (with 1% NH₃) to givethe title product (S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate(0.30g) as a white foam. TLC R_(f) =0.35 (DCM: MeOH 10:1); ¹H NMR (200 MHz,CDCl₃): δ=1.45 (s, 3H), 1.50-1.70 (m, 6H), 1.70-2.20 (m, 10H), 2.30-2.80(m, 8H), 3.71 and 3.73 (s and s, total 6H), 4.15-4.40 (m, 1H), 4.30-4.60(m, 1H), 6.62 (d, 2H, J=8.4 Hz); 6.66 (s, 1H), 7.36 (t, 1H J=8.5 Hz),7.66 (d, 1H, J=8.4 Hz); LC-MS (ESI): m/z calculated for C₃₁H₄₇N₄O₅[M+H⁺]: 555, Found: 555.3.

(S)-methyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate:To a solution of (S)-tert-butyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate(1.73 g, 5.5 mmol) in DCM (10 mL) was added TFA (2 mL, 28 mmol) andstirred at rt for 2 h. Solvent was removed to provide crude(S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoicacid as yellow solid (2.1 g), which was used as is for the next reactionwithout further purification; LC-MS (ESI): m/z calculated for C₂₇H₃₉N₄O₅[M+H⁺]: 499, Found: 499.5. To a solution of acid (120 mg, 0.24 mmol) inMeOH (2 ml) was added sulfuric acid (conc., 0.20 mL), and stirred at rtfor 15 h. The solution was quenched with NaHCO₃ (sat., 20 mL), extractedwith EtOAc (10 mL), dried (Na₂SO₄) and concentrated to give crude(S)-methyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate(0.11 g) as a colorless oil, which was used as is for the next withoutfurther purification; LC-MS (ESI): m/z calculated for C₂₇H₄₁N₆O₄ [M+H⁺]:513, Found: 513.1.

(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(1-hydrazinyl-1-oxo-5-(piperidin-1-yl)pentan-3-3yl)-1H-pyrazole-3-carboxamide:A mixture of (S)-methyl3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoate(0.11 g), NH₂NH₂. H₂₀ (1.0 ml) and EtOH (3.0 ml) was heated at 80° C.for 3 h. The solution was cooled to rt, concentrated and purified using0-15% MeOH in DCM (with 1% NH₃) to give(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(1-hydrazinyl-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1H-pyrazole-3-carboxamide(50mg) as a colorless material; ¹H NMR (200 MHz, CDCl₃): δ=1.40-2.20 (m,18H), 2.20-2.80 (m, 6H), 3.73 (s, 6H), 3.89 (br s, 2H), 4.15-4.30 (m,1H), 4.30-4.50 (m, 1H), 6.62 (d, 2H, J=8.4 Hz), 6.66 (s, 1H), 7.37 (t,1H J=8.4 Hz), 8.06 (d, 1H, J=7.4 Hz), 8.37 (br s, 1H); LC-MS (ESI): m/zcalculated for C₂₈H₄₁N₄O₅ [M+H⁺]: 513, Found: 513.1

(S)—N-(1-(1,3,4-oxadiazol-2-yl)-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide:To a solution of(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(1-hydrazinyl-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1H-pyrazole-3-carboxamide(50 mg, 0.10 mmol) in CH(OMe)₃ was added PTSA.H₂O (25 mg, 0.13 mmol).The mixture was heated at 85° C. for 2 h, cooled to rt, diluted withEtOAc (10 mL) and washed with NaHCO₃ (sat., 10 mL). The EtOAc solutionwas dried (Na₂SO₄), concentrated, and purified using 0-15% MeOH in DCM(with 1% NH₃) to give the title product(S)—N-(1-(1,3,4-oxadiazol-2-yl)-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide(30mg) as a white foam; ¹H NMR (200 MHz, CDCl₃): δ=1.40-2.20 (m, 18H),2.20-2.80 (m, 4H), 3.15-3.50 (m, 2H), 3.73 (s, 6H), 4.15-4.30 (m, 1H),4.30-4.50 (m, 1H), 6.62 (d, 2H, J=8.0 Hz), 6.65 (s, 1H), 7.37 (t, 1HJ=8.4 Hz), 7.90 (d, 1H, J=8.4 Hz), 8.36 (s, 1H); LC-MS (ESI): m/zcalculated for C₂₈H₄₀N₇O₃ [M+H⁺]: 523, Found: 523.2

(S)—N-(1-amino-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide:To a solution of(S)-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)-5-(piperidin-1-yl)pentanoicacid(1.0 g, 1.8 mmol) in pyridine (20 ml) and dioxane (20 ml) were addedammonium carbonate (0.21 g, 2.7 mmol), followed by Boc₂O (0.47 g, 2.16mmol). The progress of the reaction was monitored by LC-MS. Additionalammonium carbonate and Boc₂O (2 eq each) were added after 1 h. Stirringwas continued for 12 h, and additional ammonium carbonate and Boc₂O (2eq each) were added. After further stirring for 1 h, LC-MS indicated thecompletion of the reaction. The mixture was concentrated to dryness,quenched with NaHCO₃ (sat., 20 ml) and extracted with EtOAc (20 ml). TheEtOAc solution was dried (Na₂SO₄), concentrated, and purified using0-15% MeOH in DCM (with 1% NH₃) to give the title product(S)—N-(1-amino-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide(0.64g) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ=1.50-2.20 (m, 16H),2.20-2.80 (m, 8H), 3.15-3.50 (m, 2H), 3.72 (s, 6H), 4.15-4.30 (m, 1H),4.30-4.50 (m, 1H), 5.37 (br s, 1H), 6.62 (d, 2H, J=8.4 Hz), 6.65 (s,1H), 7.18 (br s, 1H), 7.20-7.40 (m, 2H), 7.64 (t, 1H, J=7.0 Hz), 8.13(d, 1H, J=8.4 Hz), 8.61 (d, 1H, J=4.0 Hz); LC-MS (ESI): m/z calculatedfor C₂₇H₄₀N₅O₄ [M+H⁺]: 498, Found: 498.3

(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide:A solution of(S)—N-(1-amino-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide(40 mg, 0.80 mmol) in DMF-DMA (1 ml) was heated at 120° C. for 2 h. Thesolution was concentrated to dryness and the residue was dissolved inHOAc (1.0 ml), followed by addition of NH₂NH₂. H₂₀ (0.10 ml). Theresulting solution was heated at 90° C. for 2 h, cooled to rt, quenchedwith NaHCO₃ (sat., 20 ml), and extracted with EtOAc (10 ml). The EtOAcsolution was dried (Na₂SO₄), concentrated, and purified using 0-15% MeOHin DCM (with 1% NH₃) to give the title product(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide(24mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m, 16H),2.30-2.80 (m, 6H), 3.20-3.40 (m, 2H), 3.72 (s, 6H), 4.15-4.30 (m, 1H),4.50-4.70 (m, 1H), 6.62 (d, 2H, J=8.6 Hz), 6.68 (s, 1H), 7.35 (t, 1H,J=7.5 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J=8.6 Hz); LC-MS (ESI): m/zcalculated for C₂₈H₃₉N₇O₃ [M+H⁺]: 522, Found: 522.3.

(S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide:To a solution of(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide(50 mg, 0.10 mmol) in DCM (1 ml) at rt were added Et₃N (56 μL, 0.40mmol) and trifluoroacetic anhydride (56 μL, 0.40 mmol). The solution wasstirred at rt for 15 h. LC-MS analysis showed the completion of thereaction. The mixture was quenched with NaHCO₃ (sat., 10 ml) andextracted with DCM (10 ml). The extract was dried (Na₂SO₄),concentrated, and purified using 0-10% MeOH in DCM to give the titleproduct(S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide(13mg) as a yellow solid; ¹H NMR (200 MHz, CDCl₃): δ=1.40-2.20 (m, 24H),2.79 (d, 2H, J=6.1 Hz) 3.74 and 3.75 (s and s, total 6H), 4.20-4.30 (m,1H), 4.30-4.50 (m, 1H), 6.63 (d, 2H, J=8.2 Hz); 6.67 (s, 1H), 7.38 (t,1H, J=8.4 Hz), 7.98 (br s, 1H); LC-MS (ESI): m/z calculated forC₂₇H₃₈N₅O₃ [M+H⁺]: 480, Found: 479.9.

(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(1H-tetrazol-5-yl)butan-2-yl)-1H-pyrazole-3-carboxamide:A mixture of(S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide(50 mg) and Me₃SnN₃ (71 mg) in toluene (1 ml) was heated at 100° C. for20 h. The mixture was concentrated and purified using 0-15% MeOH in DCM(with 1% NH₃) to give the title product(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(1H-tetrazol-5-yl)butan-2-yl)-1H-pyrazole-3-carboxamide(42mg) as an orange foam; ¹H NMR (200 MHz, CDCl₃): δ=1.40-2.20 (m, 24H),3.29 (d, 2H, J=4.6 Hz) 3.73 and 3.74 (s and s, total 6H), 4.20-4.40 (m,1H), 4.50-4.70 (m, 1H), 6.62 (d, 2H, J=8.4 Hz); 6.67 (s, 1H), 7.37 (t,2H, J=8.4 Hz), 9.68 (s, 1H); LC-MS (ESI): m/z calculated for C₂₇H₃₉N₈O₃[M+H⁺]: 523, Found: 522.9.

(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(thiazol-2-yl)butan-2-yl)-1H-pyrazole-3-carboxamide: A mixture of(S)—N-(1-cyano-4-(piperidin-1-yl)butan-2-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide(96 mg, 0.20 mmol), P₂S₅ (90 mg, 0.40 mmol) and EtOH (2 ml) was heatedat 80° C. for 17 h. The mixture was concentrated to dryness to give ayellow solid. The solid was triturated with DCM and filtered through ashort pad of Celite®. The filtrate was concentrated and treated withethyl 2-bromo acetate (90 μL, 0.60 mmol) in acetic acid (2 ml) at 60° C.for 1 h, 70° C. for 1 h and 80° C. for 1 h. The mixture was cooled tort, and diluted with EtOAc (20 ml), washed with NaHCO₃ (20 ml×2), dried(Na₂SO₄), concentrated, and purified using 0-15% MeOH in DCM (with 1%NH₃) to give(S)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-(4-(piperidin-1-yl)-1-(thiazol-2-yl)butan-2-yl)-1H-pyrazole-3-carboxamide(20 mg) as a yellow oil; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.00 (m, 14H),2.30-2.60 (m, 6H), 3.30-3.50 (m, 2H), 3.40-3.70 (m, 2H), 3.73 (s, 6H),4.20-4.35 (m, 1H), 4.50-4.70 (m, 1H), 6.62 (d, 2H, J=8.4 Hz); 6.67 (s,1H), 7.22 (d, 1 H, J=3.2 Hz), 7.36 (t, 1H, J=8.4 Hz), 7.70 (d, 1 H,J=3.4 Hz), 7.99 (d, 1 H, J=5.8 Hz); LC-MS (ESI): m/z calculated forC₂₉H₄₀N₅O₃S [M+H⁺]: 538, Found: 537.8.

Reagents and conditions: (a) MeOH, H₂SO₄, 75° C., 18h; (b) hydrazinemonohydrate, EtOH, 85° C., 8 h; (c) amidine.HCl, KOtBu (1.0 M in THF),BuOH, 120° C., 4 h; (d) ammonium carbonate, Boc₂O, pyridine, dioxane, 12h; (e) POC_(13,) imidazole, pyridine, 5° C., 1 h; (f) P₂S₅, EtOH, 85°C., rt, 17 h; (g) trifluoroacetyl hydrazide, toluene, 110° C., 4 h;1,2-dichloro benzene, 160° C., 17 h.

(S)-methyl3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate:To a solution of(S)-3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid hydrochloride (0.50 g) in MeOH (10 ml) was added sulfuric acid(con., 0.30 mL). The solution was heated at 50° C. for 1 h and 75° C.for 18 h. The mixture was diluted with EtOAc and washed with NaHCO₃. TheEtOAc layer was dried (Na₂SO₄), and concentrated to give crude(S)-methyl3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate(0.41g) as a white foam; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m, 14H),2.30-2.80 (m, 8H), 3.67 (s, 3H), 4.20-4.40 (m, 1H), 4.40-4.60 (m, 1H),6.68 (s, 1H), 7.20-7.60 (m, 5H); LC-MS (ESI): m/z calculated forC₂₆H₃₄F₂C₁N₄O₃ [M+H⁺]: 523 and 525, Found: 523.1 and 525.2.

(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(5-(3,3-difluoropiperidin-1-yl)-1-hydrazinyl-1-oxopentan-3-yl)-1H-pyrazole-3-carboxamide:A mixture of (S)-methyl3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate(0.40 g), hydrazine monohydrate (1.0 ml) and EtOH (5 ml) was refluxed at85° C. for 4 h. Additional hydrazine monohydrate (2.0 ml) was added, andrefluxed at 90° C. for 4 h. LC-MS indicated the completion of thereaction. The mixture was concentrated to dryness, and purified using0-15% MeOH in DCM (with 1% NH₃) to give(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(5-(3,3-difluoropiperidin-1-yl)-1-hydrazinyl-1-oxopentan-3-yl)-1H-pyrazole-3-carboxamide(0.35 g) as a white foam; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m, 14H),2.30-2.80 (m, 8H), 4.20-4.50 (m, 2H), 6.72 (s, 1H), 7.20-7.60 (m, 4H),7.65 (s, 1H), 7.72 (d, 1H, J=8.4 Hz); LC-MS (ESI): m/z calculated forC₂₅H₃₄ClN₆O₂ [M+H⁺]: 523 and 525, Found: 522.7 and 524.9.

(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide:To a suspension of(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(5-(3,3-difluoropiperidin-1-yl)-1-hydrazinyl-1-oxopentan-3-yl)-1H-pyrazole-3-carboxamide(104 mg, 0.20 mmol), amidine.HCl (58 mg, 0.60 mmol) in BuOH (20 ml) wasadded KOtBu (0.60 ml, 1.0M in THF, 0.60 mmol). The mixture was heated at120° C. for 4 h, cooled to rt, diluted with water (10 ml) and extractedwith EA (10 ml). The extract was dried (Na₂SO₄), concentrated, andpurified using 0-10% MeOH in DCM (with 1% NH₃) to give(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-methyl-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide(90 mg) as a white foam; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m, 14H),2.41 (s, 3H), 2.42-2.80 (m, 6H), 3.05-3.20 (m, 2H), 4.20-4.40 (m, 1H),4.50-4.70 (m, 1H), 6.73 (s, 1H), 7.26-7.60 (m, 4H), 7.80-7.95 (m, 1H);LC-MS (ESI): m/z calculated for C₂₇H₃₅C₁F₂N₇O [M+H⁺]: 546 and 548,Found: 545.7 and 547.9.

(S)—N-(1-amino-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide:To a solution of(S)-3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid hydrochloride (1.6 g, 2.76 mmol) in pyridine (40 ml) and dioxane(40 ml) was added Boc₂O (0.60 g, 2.76 mmol), followed by ammoniumcarbonate (0.22 g, 2.76 mmol). The progress of the reaction wasmonitored by LC-MS. Additional ammonium carbonate and Boc₂O (2 eq each)were added after 1 h. Stirring was continued for 12 h, and additionalammonium carbonate and Boc₂O (2 eq each) were added. After furtherstirring for 1 h, LC-MS indicated the completion of the reaction. Themixture was concentrated to dryness, quenched with NaHCO₃ (sat., 40 ml)and extracted with EtOAc (40 mL). The EtOAc solution was dried (Na₂SO₄),concentrated, and purified using 0-15% MeOH in DCM (with 1% NH₃) to givethe title product(S)—N-(1-amino-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide(1.30g) as a white foam; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m, 14H),2.30-2.80 (m, 8H), 4.20-4.60 (m, 2H), 5.33 (br s, 1H), 6.50 (br s, 1H),6.72 (s, 1H), 7.20-7.60 (m, 4H), 7.71 (d, 1H, J=9.0 Hz); LC-MS (ESI):m/z calculated for C₂₅H₃₃C₁N₅O₂ [M+H⁺]: 508 and 510, Found: 508.0 and510.1.

(S)-5-(2-chlorophenyl)-N-(1-cyano-4-(3,3-difluoropiperidin-1-yl)butan-2-yl)-1-cyclopentyl-1H-pyrazole-3-carboxamide:To a mixture of(S)—N-(1-amino-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide(0.80 g, 1.6 mmol) and imidazole (109 mg, 1.6 mmol) in pyridine (15 ml)at 5° C. was added dropwise of POCl₃ (0.30 ml, 3.2 mmol). Afteraddition, the mixture was continued to stir at 5° C. for 1 h before itwas quenched with NaHCO₃, and extracted with EtOAc. The EtOAc solutionwas dried (Na₂SO₄), concentrated, and purified using 0-10% MeOH in DCM(with 1% NH₃) to give the title product(S)-5-(2-chlorophenyl)-N-(1-cyano-4-(3,3-difluoropiperidin-1-yl)butan-2-yl)-1-cyclopentyl-1H-pyrazole-3-carboxamide(0.80 g) as a brown oil(contaminated with pyridine); ¹H NMR (200 MHz, CDCl₃): δ1.70-2.20 (m,14H), 2.40-2.80 (m, 6H), 2.86 (d, 2H, J=5.0 Hz), 4.20-4.50 (m, 2H), 6.74(s, 1H), 7.20-7.60 (m, 5H); LC-MS (ESI): m/z calculated forC₂₅H₃₁C₁F₂N₅O [M+H⁺]: 490 and 492, Found: 489.9 and 492.2.

(S)-methyl3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanimidothioate:A mixture of(S)-5-(2-chlorophenyl)-N-(1-cyano-4-(3,3-difluoropiperidin-1-yl)butan-2-yl)-1-cyclopentyl-1H-pyrazole-3-carboxamide(0.80 g, 1.5 mmol), P₂S₅ (1.0 g, 4.5 mmol) and EtOH (15 ml) was heatedat 85° C. for 17 h. It was cooled to rt, diluted with EtOAc and washedwith NaHCO₃. The EtOAc layer was dried (Na₂SO₄) and concentrated to givea yellow foam.

To a mixture of the above yellow foam (0.53 g, about 1.0 mmol), K₂CO₃(0.55g, 4.0 mmol) and acetone (10 ml) was added MeI (0.25 ml, 4.0 mmol).The mixture was stirred at rt for 1.5 h before quenched with water andEA. The EtOAc layer was separated, dried (Na₂SO₄) and concentrated togive crude (S)-methyl3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanimidothioate(0.53g) as a brown oil.

(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide:A mixture of (S)-methyl3-(5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanimidothioate(0.12 g, 0.24 mmol), trifluoroacetyl hydrazide (30 mg, 0.24 mmol) andtoluene (3 ml) was heated at 110° C. for 4 h. LC-MS showed littleprogress. Then 1,2-dichloro benzene was added, and the mixture washeated at 160° C. for 17 h. It was cooled to rt, concentrated to drynessand purified to give(S)-5-(2-chlorophenyl)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-1-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)butan-2-yl)-1H-pyrazole-3-carboxamide(20 mg) as an off-white foam; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m,14H), 2.30-2.80 (m, 6H), 3.10-3.40 (m, 2H), 4.20-4.40 (m, 2H), 4.60-4.80(m, 1H), 6.75 (s, 1H), 7.20-7.60 (m, 4H), 7.72 (d, 1H, J=8.4 Hz); LC-MS(ESI): m/z calculated for C₂₇H₃₂C₁F₅N₇O [M+H⁺]: 600 and 602, Found:599.9 and 602.0.

General Procedure for the Synthesis of (S)-tert-butyl3-amino-5-(difluoropiperidin-1-yl)pentanoates

Step 1: To a solution of difluoropiperidine.HCl (1 eq) in water (1mL/mmol of piperidine) was added Na₂CO₃ (1 eq), and stirred at rt for 10min. THF (2 mL/mmol of piperidine) was added, and the mixture was cooledto −15° C. DBU (1%) was added, followed by acrolein (90%, 1 eq). Afteraddition, the mixture was stirred at −15° C. for 30 min, and thecompound 3-(difluoropiperidin-1-yl)propanal in THF and water was used asis for the next step.

Step2: To a solution of t-butyl diethylphosphonoacetate (1.2 eq todilfluoropiperidine) in THF (1 mL/mmol of phosphonoacetate) at rt wasadded KOtBu (1.2 eq to 1 eq of dilfluoropiperidine). The mixture wasstirred at rt for 10 min and then cooled to 5° C. Then, the solution3-(difluoropiperidin-1-yl)propanal was added, and the resulting mixturewas slowly warmed to rt. Stirring was continued at rt for 2 h before themixture was quenched with water extracted with hexanes/EtOAc. Theextract was dried (Na₂SO₄), concentrated and purified using 0-10% EtOAcin Hexanes to give compound (E)-tert-butyl5-(difluoropiperidin-1-yl)pent-2-enoate.

Step 3: To a solution of (S)-(N)-benzyl-1-phenylethylamine (1.5 eq) inTHF (2 mL/mmol of amine) at −75° C. was added slowly n-BuLi (1.5 eq).Stirring was continued at −75° C. for 30 min before dropwise addition ofa solution of (E)-tert-butyl 5-(difluoropiperidin-1-yl)pent-2-enoate (1eq) in THF (1 ml/mmol of amine). After addition, the mixture wascontinued to stir at −75° C. for 3 h, quenched with citric acid, andextracted with hexanes. The extract was dried (Na₂SO₄), concentrated andpurified using 0-10% EtOAc in Hexanes to give (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(difluoropiperidin-1-yl)pentanoate.

Step 4: A mixture of (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(difluoropiperidin-1-yl)pentanoate(1eq), Pd/C (10% on carbon, 0.3 eq by mass) and MeOH (50 ml/ g of amine)was hydrogenated under H₂ (50 Psi) using a Parr-Shaker at rt for 3 daysuntil the completion of reaction monitored by LC-MS analysis. Themixture was then quenched with celited, and filtered through a short-padof Celite®, concentrated to give crude (S)-tert-butyl3-amino-5-(difluoropiperidin-1-yl)pentanoate.

(E)-tert-butyl 5-(3,3-difluoropiperidin-1-yl)pent-2-enoate: Using thegeneral procedure (Step 1 and 2) described above,3,3-difluoropipiridine.HCl (4.36 g, 27.7 mmol) was used to give(E)-tert-butyl 5-(3,3-difluoropiperidin-1-yl)pent-2-enoate (1.96 g) as acolorless oil after column purification using 0-10% EtOAc in Hexanes; ¹HNMR (200 MHz, CDCl₃): δ1.57 (s, 9H), 1.60-2.00 (m, 4H), 2.30-2.80 (m,8H), 5.78 (m, 1H), 6.82 (m, 1H); LC-MS (ESI): m/z calculated forC₁₄H₂₆NO₂ [M+H⁺]: 240, Found: 240.1.

(E)-tert-butyl 5-(4,4-difluoropiperidin-1-yl)pent-2-enoate: Using thegeneral procedure (Step 1 and 2) described above,4,4-difluoropipiridine.HCl (5.0g, 31.7 mmol) was used to give(E)-tert-butyl 5-(4,4-difluoropiperidin-1-yl)pent-2-enoate (3.59 g) aswhite solid after column purification using 0-10% EtOAc in Hexanes;¹HNMR (200 MHz, CDCl₃): δ1.50 (s, 9H), 1.80-2.20 (m, 4H), 2.30-2.60 (m,8H), 5.78 (m, 1H), 6.82 (m, 1H); LC-MS (ESI): m/z calculated forC₁₄H₂₄F₂NO₂ [M+H⁺]: 276, Found: 275.8.

(S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(3,3-difluoropiperidin-1-yl)pentanoate:Using the general procedure (Step 3) described above, (E)-tert-butyl5-(3,3-difluoropiperidin-1-yl)pent-2-enoate(1.96 g, 7.1 mmol) was usedto give (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(3,3-difluoropiperidin-1-yl)pentanoate(1.87 g) as a white solid after column purification using 0-10% EtOAc inHexanes. ¹H NMR (200 MHz, CDCl₃): δ1.35 (d, 3H, J=7.4 Hz), 1.45 (s, 9H),1.50-2.00 (m, 8H), 2.30-2.80 (m, 6H), 3.30-3.40 (m, 1H), 3.48 (d, 1H,J=15.0 Hz), 3.70-3.90 (m, 2H), 7.15-7.45 (m, 10H); LC-MS (ESI): m/zcalculated for C₂₉H₄₁F₂N₂O₂ [M+H⁺]: 487, Found: 486.7.

(S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(4,4-difluoropiperidin-1-yl)pentanoate:Using the general procedure (Step 3) described above, (E)-tert-butyl5-(4,4-difluoropiperidin-1-yl)pent-2-enoate (4.0 g, 19.1 mmol) was usedto give (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(4,4-difluoropiperidin-1-yl)pentanoate(3.78 g) as a colorless oil after column purification using 0-10% EtOAcin Hexanes.¹H NMR (200 MHz, CDCl₃): δ1.34 (d, 3H, J=7.0 Hz), 1.42 (s,9H), 1.40-1.60 (m, 2H), 1.80-2.10 (m, 6H), 2.30-2.70 (m, 6H), 3.30-3.40(m, 1H), 3.48 (d, 1H, J=15.0 Hz), 3.70-3.90 (m, 2H), 7.15-7.45 (m, 10H);LC-MS (ESI): m/z calculated for C₂₉H₄₁F₂N₂O₂ [M+H⁺]: 487, Found: 486.6

(S)-tert-butyl 3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate: Usingthe general procedure (Step 4) described above, (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(3,3-difluoropiperidin-1-yl)pentanoate(1.9 g, 3.9 mmol) was used to give crude (S)-tert-butyl3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate (1.29 g) as a whitefoam,¹H NMR (200 MHz, CDCl₃): δ1.43 (s, 9H), 1.70-2.40 (m, 8H),2.60-3.20 (m, 7H), 3.60-3.80 (m, 1H); LC-MS (ESI): m/z calculated forC₁₄H₂₈F₂N₂O₂ [M+H⁺]: 293, Found: 292.8.

(S)-tert-butyl 3-amino-5-(4,4-difluoropiperidin-1-yl)pentanoate: Usingthe general procedure (Step 4) described above, (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(4,4-difluoropiperidin-1-yl)pentanoate(9.3 g, 19.1 mmol) was used to give crude (S)-tert-butyl3-amino-5-(4,4-difluoropiperidin-1-yl)pentanoate (5.5 g) as a whitesolid; 81.45 (s, 9H), 1.70-2.40 (m, 8H), 2.50-3.20 (m, 7H), 3.60-3.80(m, 1H); LC-MS (ESI): m/z calculated for C₁₄H₂₈F₂N₂O₂ [M+H⁺]: 293,Found: 292.8.

(S)-tert-butyl3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate:A mixture of1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxylicacid (70 mg, 0.24 mmol), (S)-tert-butyl3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate (58 mg, 0.20 mmol),Et₃N (81 μl, 0.80 mmol) and TBTU (96 mg, 0.30 mmol) in MeCN (4 ml) wasstirred at rt for 15 h. The mixture was diluted with EtOAc and washedwith NaHCO₃. The organic layer was dried (Na₂SO₄), concentrated, andpurified using EtOAc/Hex to give (S)-tert-butyl3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate(50mg) as a colorless oil; ¹H NMR (200 MHz, CDCl₃): δ1.44 (s, 9H),1.60-2.20 (m, 15H), 2.10-2.80 (m, 10H), 4.00-4.20 (m, 1H), 4.30-4.50 (m,1H), 6.67 (s, 1H), 7.19 (d, 1H, J=6.2 Hz), 7.30-7.60 (m, 3H), 7.60-7.80(m, 1H); LC-MS (ESI): m/z calculated for C₃₁H₄₃F₄N₄O₃ [M+H⁺]: 595,Found: 594.9

(S)-3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid: To a solution of(S)-tert-butyl3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate(50 mg, 0.096 mmol) in DCM (2 mL) was added TFA (0.5 mL) and stirred atrt for 2 h. Solvent was removed in vacuo and diluted with CHCl₃. Solventwas removed to provide(S)-3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid (38 mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ1.40-2.20 (m,18H), 2.40-2.80 (m, 7H), 4.00-4.20 (m, 1H), 4.30-4.50 (m, 1H), 6.67 (s,1H), 7.19 (d, 1H, J=7.6 Hz), 7.40-7.80 (m, 3H); LC-MS (ESI): m/zcalculated for C₂₇H₃₅F₄N₄O₃ [M+H⁺]: 539, Found: 538.7.

(S)-1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-N-(5-(3,3-difluoropiperidin-1-yl)-1-oxo-1-(thiazol-2-ylamino)pentan-3-yl)-1H-pyrazole-3-carboxamide:A mixture of(S)-3-(1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid (35 mg, 0.065 mmol), 2-aminothiazole (13 mg, 0.13 mmol), Et₃N (36μL, 0.26 mmol) and TBTU (42 mg, 0.13 mmol) in DMF (1 ml) was stirred atrt for 15 h. The mixture was diluted with EtOAc and washed with water.The organic layer was dried (Na₂SO₄), concentrated, and purified using0-100% EtOAc in hexanes to give the desired product(S)-1-cyclopentyl-5-(2-(1,1-difluoroethyl)phenyl)-N-(5-(3,3-difluoropiperidin-1-yl)-1-oxo-1-(thiazol-2-ylamino)pentan-3-yl)-1H-pyrazole-3-carboxamide(18 mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ 1.40-2.20 (m, 18H),2.40-2.80 (m, 7H), 4.00-4.20 (m, 1H), 4.40-4.60 (m, 1H), 6.70 (s, 1H),6.97 (d, 1H, J=3.8 Hz), 7.19 (d, 1H, J=6.6 Hz), 7.40-7.60 (m, 3H), 7.67(d, 1H, J=6.6 Hz), 7.81 (d, 1H, J=8.0 Hz), 11.5 (br s, 1H); LC-MS (ESI):m/z calculated for C₃₀H₃₇F₄N₆O₂S [M+H⁺]: 621, Found: 620.9.

(S)—N-(1-(cyclobutylamino)-5-hydroxy-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:A mixture of (S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxypentanoate(0.15 g), cyclobutylamine (0.50 ml) and EtOH (1 mL) was heated in asealed tube at 90° C. for 24 h. The mixture was concentrated andpurified using EtOAc in hexanes (0-25%) to give(S)—N-(1-(cyclobutylamino)-5-hydroxy-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(97 mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ 0.80-0.95 (m, 2H),1.40-2.70 (m, 16H), 3.60-3.80 (m, 2H), 4.04-4.20 (m, 1H), 4.20-4.45 (m,1H), 4.50-4.70 (m, 1H), 6.18 (br s, 1H), 6.73 (s, 1H), 7.25-7.40 (m,1H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1H), 7.98 (br s, 1H); LC-MS (ESI):m/z calculated for C₂₅H₃₂F₃N₄O₃ [M+H⁺]: 493, Found: 493.1.

(S)—N-(1-(cyclobutylamino)-1,5-dioxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:To a solution of(S)—N-(1-(cyclobutylamino)-5-hydroxy-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(90 mg, 0.18 mmol) in DCM (2 mL) was added Dess-Martin Reagent (153 mg,0.36 mmol). The mixture was stirred at rt for 0.5 h before it wasquenched with sodium thiosulfate (10%) and NaHCO₃. The mixture wasextracted with DCM, and the extract was dried (Na₂SO₄), concentrated andpurified using EtOAc in hexanes (0-20%) to give(S)—N-(1-(cyclobutylamino)-1,5-dioxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(32 mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ 1.29 (t, 2H,J=7.0Hz), 1.40-2.70 (m, 15H), 2.90-3.10 (m, 1H), 4.04-4.20 (m, 1H), 4.50-4.6(m, 1H), 4.65-4.90 (m, 1H), 5.28 (br s, 1H), 6.73 (s, 1H), 6.84 (d, 1H,J=7.8 Hz), 7.25-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.85 (m, 1H), 9.81(s, 1H); LC-MS (ESI): m/z calculated for C₂₅H₃₀F₃N₄O₃ [M+H⁺]: 491,Found: 490.6.

(S)—N-(1-(cyclobutylamino)-5-(cyclopentyl(methylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide

To a mixture of crude aldehyde,(S)—N-(1-(cyclobutylamino)-1,5-dioxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(74 mg, 0.150 mmol) and N-methylcyclopentanamine (30 mg, 0.300 mmol) inMeOH (4 mL) was added sodium cyanoborohydride (19 mg, 0.300 mmol). Theresulting mixture was stirred at rt for 1-3 h until the completion ofthe reaction by LC-MS analysis. Then mixture was concentrated andpurified using MeOH in DCM (with 1% NH₃) to give(S)—N-(1-(cyclobutylamino)-5-(cyclopentyl(methyl)amino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(23 mg) as a colorless oil; ¹H NMR (200 MHz, CDCl₃): δ 1.40-2.90 (m,31H), 4.04-4.20 (m, 1H), 4.20-4.50 (m, 2H), 6.74 (s, 1H), 7.03 (br s,1H), 7.14 (br s, 1H), 7.25-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90(m, 1H), 8.56 (br s, 1H); LC-MS (ESI): m/z calculated for C₃₁H₄₃F₃N₅O₂[M+H⁺]: 574, Found: 573.9.

Preparation of Zn(N₃)₂.Py₂: To a solution of Zn(NO₃)₂ (3.57 g, 12 mmol)in water (6 mL) was added a solution of sodium azide (0.78 g, 12.0 mmol)in water (6 mL). The mixture was stirred at rt for 5 min and heated to50° C., followed by dropwise addition of pyridine (2.0 mL, 24.7 mmol).After addition, the oil bath was removed, and stirring was continued for1 h to give a cloudy mixture. The suspension was filtered, washed withcold water (5 mL) and air dried to give the title compound (1.3 g) as awhite solid.

(S)-tert-butyl5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoate:To a mixture of (S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxypentanoate(2.5 g, 5.0 mmol), Zn(N₃)₂.Py₂ (1.15 g, 3.75 mmol), PPh₃ (2.62 g, 10.0mmol) and toluene (50 mL) was added dropwise of DIAD (2.0 mL, 10 mmol)and stirred at rt for 20 h. The mixture was filtered, rinsed with EtOAc,and the filtrate was concentrated and purified using EtOAc in hexanes(0-40%) to give (S)-tert-butyl5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoate(2.04 g) as a white semi-solid; ¹H NMR (200 MHz, CDCl₃): δ 1.46 (s, 9H),1.50-1.60 (m, 2H), 1.80-2.10 (m, 8H), 2.55-2.65(m, 2H), 3.45 (t, 2H,J=7.1 Hz), 4.40-4.60 (m, 1H), 4.85-5.05 (m, 1H), 6.31 (br s, 1H), 6.76(s, 1H), 7.28-7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1H); LC-MS(ESI): m/z calculated for C₂₅H₃₂F₃N₆O₃ [M+H⁺]: 521, Found: 520.9.

(S)—N-(5-azido-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:To a solution of (S)-tert-butyl5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoate(99 mg, 0.190 mmol) in DCM (2 mL) was added TFA (0.15 mL, 1.90 mmol) andstirred at rt for 2 h. Solvent was removed to provide crude(S)-5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoicacid (100 mg) as yellow oil which was used as is for the next reactionwithout further purification.

To a solution of(S)-5-azido-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)pentanoicacid(100 mg, 0.215 mmol)and cyclobutylamine (30 mg, 0.430 mmol) in ACN(1 mL) was added anhydrous NEt₃ (0.090 mL, 0.645 mmol) followed by TBTU(138 mg, 0.430 mmol). The reaction mixture was stirred at rt for 18 h.Reaction mixture was diluted with EtOAc (10 mL) and washed with sat.NaHCO₃ (5 mL). Organic phase was extracted, added silica gel (100 mg)and purified using Combiflash® R_(f) (EtOAc/hexanes) and the fractionscontaining the product (TLC) were pooled and evaporated to afford 35 mgof(S)—N-(5-azido-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamideas a white foam; ¹H NMR (200 MHz, CDCl₃): δ 1.40-2.40 (m, 16H),2.55-2.65 (m, 2H), 3.44 (t, 2H, J=7.6 Hz), 4.10-4.50 (m, 3H), 6.64 (brs, 1H), 6.75 (s, 1H), 7.28-7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.70-7.90(m, 1H); LC-MS (ESI): m/z calculated for C₂₅H₃₀F₃N₇O₂ [M+H⁺]: 518,Found: 518.2.

(S)—N-(5-amino-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:A mixture of(S)—N-(5-azido-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(35 mg) Pd/C (10%, 7 mg) and EtOH (3 mL) was stirred under a balloon ofhydrogen for 17 h. LC-MS showed the completion of the reduction. Thenthe mixture was filtered through a short pad of Celite®, and thefiltrate was concentrated to give crude(S)—N-(5-amino-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamideas a colorless oil (30 mg); LC-MS (ESI): m/z calculated for C₂₅H₃₃F₃N₅O₂[M+H⁺]: 492, Found: 492.2.

(S)—N-(1-(cyclobutylamino)-5-(oxetane-3-carboxamido)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:To a solution of(S)—N-(5-amino-1-(cyclobutylamino)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(30 mg, 0.061 mmol) and 3-oxetanecarboxylic acid (13 mg, 0.122 mmol) inACN (2 mL) was added anhydrous NEt₃ (0.018 mL, 0.183 mmol) followed byTBTU (39 mg, 0.122 mmol). The reaction mixture was stirred at rt for 18h. The reaction mixture was diluted with EtOAc (10 mL) and washed withsat. NaHCO₃ (5 mL). The organic phase was extracted, added silica gel(100 mg) and purified using Combiflash® R_(f) (EtOAc/hexanes) and thefractions containing the product (TLC) were pooled and evaporated toafford(S)—N-(1-(cyclobutylamino)-5-(oxetane-3-carboxamido)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide(6mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ 1.40-2.80 (m, 19H),3.60-3.90 (m, 2H), 4.10-4.50 (m, 3H), 4.70-5.00 (m, 4H). 6.32 (br s,1H), 6.71 (s, 1H), 7.18 (br s, 1H), 7.28-7.40 (m, 1H), 7.50-7.70 (m,2H), 7.70-7.90 (m, 1H), 8.15 (d, 1H, J=8.8 Hz); LC-MS (ESI): m/zcalculated for C₂₉H₃₇F₃N₅O₄ [M+H⁺]: 576, Found: 576.2.

(S)-methyl3-4((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-hydroxybutanoate:

N-methylmorpholine (4.46 mL, 40.6 mmol, 1.00 equiv.) was added to asolution of(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutanoicacid in DME (81 mL) at −15° C. Isobutylchloroformate (5.27 mL, 40.6mmol, 1.00 equiv.) was then added dropwise. The reaction mixture wasstirred at the same temperature for 1 h. The solution was filtered on afrit and the filtrate cooled back to −15° C. A solution of sodiumborohydride (2.30 g, 60.9 mmol, 1.50 equiv.) in water (20 mL) was added.Right after this addition, 800 mL of water was added (a whiteprecipitate formed). The solution was filtered, the solid was ground toa fine powder and dried under reduced pressure to provide 9.13 g (63%)of the title compound as a white solid mixed with some of thecorresponding lactonized product. m/z (M+H)⁺=356.1; R_(T)=1.51 min;purity=65%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B -100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A:pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.

(S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutanoate: Iodine(5.46 g, 21.5 mmol, 1.00 equiv.) was added to a solution oftriphenylphosphine (5.65 g, 21.5 mmol, 1.00 equiv.) and imidazole (1.76g, 25.8 mmol, 1.20 equiv.) in DCM (86 mL) at 0° C. The reaction mixturewas stirred for 20 min at the same temperature and the alcohol wasadded. The reaction mixture was stirred at rt for 18 h. An aqueoussaturated solution of Na₂S₂O₃ was added and the mixture was stirred for10 min and extracted with ethyl acetate (2×). The combined organiclayers were dried with sodium sulfate, filtered and evaporated. Thecrude product was purified by flash chromatography on silica gel (drypacking) using a solution of ethyl acetate in hexane (5 to 30%) toprovide 1.27 g (13%) of the title compound as a white solid and 4.0 g ofa mixture of the title compound and an impurity (LCMS ratio=58:42). Purecompound: m/z (M+H)⁺=466.0; R_(T)=1.86 min; purity=94%. HPLC conditions:Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formatein Water; Eluent B: Acetonitrile, ¹H NMR (500 MHz, DMSO) δ2.57-2.53 (m,1H), 2.64 (dd, J=15.8, 5.3 Hz, 1H), 3.27 (dd, J=10.0, 6.9 Hz, 1H), 3.37(dd, J=10.1, 5.2 Hz, 1H), 3.58 (s, 3H), 3.90-3.81 (m, 1H), 4.23 (t,J=6.9 Hz, 1H), 4.37-4.27 (m, 2H), 7.33 (td, J=7.5, 1.1 Hz, 2H), 7.42 (t,J=7.4 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.5 Hz, 2H), 7.89 (d,J=7.5 Hz, 2H).

(S)-methyl3-(4(9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(acetylthio)butanoate:Potassium thioacetate (393 mg, 3.44 mmol, 2.00 equiv.) was added to asolution of (S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutanoate in DMF(6.9 mL). The reaction mixture was stirred for 15 h. An aqueoussaturated solution of sodium bicarbonate was added, followed by ethylacetate. The phases were separated and the organic layer was washed 2×with sat'd aq. NaHCO₃, dried with sodium sulfate, filtered andevaporated. The crude product was purified by flash chromatography onsilica gel using a solution of ethyl acetate in hexane (5 to 40%) toprovide 555 mg (78%) of the title compound as a white solid. m/z(M+H)⁺=414.1; R_(T)=1.76 min; purity=99.3%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile, ¹H NMR (500 MHz, DMSO) δ2.32 (s, 3H), 2.54-2.52(m, 2H), 2.90 (dd, J=13.5, 7.7 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz, 1H),3.57 (s, 3H), 3.96-3.89 (m, 1H), 4.21 (t, J=7.0 Hz, 1H), 4.32-4.27 (m,2H), 7.33 (td, J=7.4, 1.1 Hz, 2H), 7.45-7.39 (m, 3H), 7.67 (d, J=7.4 Hz,2H), 7.89 (d, J=7.5 Hz, 2H).

(S)-2-(4(9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutane-1-sulfonicacid:

A 30% w/w solution of hydrogen peroxide in water (1.3 mL) was added toformic acid (5.0 mL) at 0° C. The reaction mixture was stirred at thattemperature for 1 h. A suspension of (S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(acetylthio)butanoate informic acid (4.0 mL) was added. The reaction mixture was stirred at rt18. The solvent was evaporated and then the crude product wasco-evaporated with toluene and a mixture of DCM/toluene to provide 554mg (98%) of the title compound as a pale orange solid. m/z (M+H)⁺=420.1;R_(T)=1.31 min; purity=87.7%. HPLC conditions: Column: XBridge® C18, 3.5μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B:Acetonitrile, ¹H NMR (500 MHz, DMSO) δ2.54-2.51 (m, 1H), 2.65-2.59 (m,1H), 2.71-2.65 (m, 1H), 3.06 (dd, J=15.8, 5.0 Hz, 1H), 3.55 (s, 3H),4.13-4.08 (m, 1H), 4.28-4.18 (m, 3H), 7.19-7.12 (m, 1H), 7.27-7.22 (m,1H), 7.32 (t, J=7.4 Hz, 2H), 7.41 (dd, J=7.4, 6.5 Hz, 2H), 7.66 (d,J=7.5 Hz, 2H), 7.88 (d, J=7.5 Hz, 2H).

(S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(chlorosulfonyl)butanoate:

Thionyl chloride (1.4 mL, 20 mmol, 15 equiv.), containing three drops ofDMF, was added to(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutane-1-sulfonicacid (554 mg, 1.32 mmol, 1.00 equiv.). The reaction mixture was stirredat rt for 3 days and was heated at 40° C. for 1.5 h. Volatiles wereevaporated and the mixture was co-evaporated 2× with DCM to provide 550mg (95%) of the title compound as a dark orange solid. m/z (M+H)⁺=438.1;R_(T)=1.77 min; purity=94.8%. HPLC conditions: Column: XBridge® C18, 3.5μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B:Acetonitrile.¹H NMR (500 MHz, DMSO) δ2.68 (dd, J=13.4, 4.5 Hz, 1H),2.54-2.48 (m, J=7.7 Hz, 1H), 2.62 (dd, J=13.8, 7.8 Hz, 1H), 3.06 (dd,J=15.7, 5.0 Hz, 1H), 3.55 (s, 3H), 4.15-4.07 (m, 1H), 4.27-4.18 (m, 3H),7.26 (d, J=7.9 Hz, 1H), 7.32 (t, J=7.5 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H),7.66 (d, J=7.0 Hz, 2H), 7.88 (d, J=7.5 Hz, 2H).

(S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoate: Aconcentrated aqueous solution of ammonium hydroxyde (0.22 mL, 3.1 mmol,5.0 equiv.) was added to a solution of (S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(chlorosulfonyl)butanoate(275 mg, 0.628 mmol, 1.00 equiv.) in THF (3.1 mL). The reaction mixturewas stirred for 2 min and the solvent was evaporated. The crude productwas purified by flash chromatography on silica gel using a solution ofethyl acetate in hexanes (5 to 60%) to provide 140 mg (53%) of the titlecompound as a pale orange solid. m/z (M+H)⁺=419.1; R_(T)=1.52 min;purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B -100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A:pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.¹H NMR(500 MHz, DMSO) δ 2.64-2.58 (m, 1H), 2.80 (dd, J=15.8, 4.7 Hz, 1H), 3.18(dd, J=14.0, 6.9 Hz, 1H), 3.25 (dd, J=14.0, 6.0 Hz, 1H), 3.58 (s, 3H),4.31-4.19 (m, 4H), 6.92 (s, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.42 (t, J=7.3Hz, 2H), 7.49 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.5Hz, 2H).

(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoicacid: HCl (conc., 1.1 mL) was added to a solution of (1)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoate (140mg, 0.335 mmol, 1.00 equiv.) in AcOH (11 mL). The reaction mixture washeated at 100° C. for 15 h. The reaction mixture was poured in 70 mL ofwater and ethyl acetate was added. The phases were separated and theorganic layer was dried with sodium sulfate, filtered and evaporated.The crude mixture was co-evaporated with dioxane and DCM to provide 122mg (90%) of the title compound as a pale yellow solid. m/z (M+H)⁺=405.2;R_(T)=1.45 min; purity=96.6%. HPLC conditions: Column: XBridge® C18, 3.5μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B:Acetonitrile.

(S)-(9H-fluoren-9-yl)methyl(4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-yl)carbamate:HATU (126 mg, 0.332 mmol, 1.10 equiv.) was added to a solution of(I)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfamoylbutanoicacid (122 mg, 0.302 mmol, 1.00 equiv.), HOAt (41 mg, 0.30 mmol, 1.0equiv.), 3,3-difluoropiperidine hydrochloride (95 mg, 0.60 mmol, 2.0equiv.) and diisopropylethylamine (0.16 mL, 0.91 mmol, 3.0 equiv.) inDMF (1.2 mL) at 0° C. The reaction was stirred at rt for 3 days. Waterwas added, followed by ethyl acetate. The phases were separated and theorganic layer was washed with satd. aq. NaHCO₃ (3x), dried with sodiumsulfate, filtered and evaporated. The crude product was purified byflash chromatography on silica gel using a solution of MeOH in DCM (0 to5%) to provide 136 mg (89%) of the title compound as a pale orangesolid. m/z (M+H)⁺=508.2; R_(T)=1.65 min; purity=97.2%. HPLC conditions:Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formatein Water; Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.62-1.53 (m,1H), 1.70-1.63 (m, 1H), 2.09-1.98 (m, 3H), 2.09-1.98 (m, 3H), 2.77-2.70(m, 1H), 3.30-3.18 (m, J=7.1 Hz, 3H), 3.46-3.42 (m, 1H), 3.82-3.71 (m,2H), 4.24-4.18 (m, 1H), 4.32-4.26 (m, 3H), 6.88 (d, J=5.5 Hz, 2H),7.35-7.30 (m, 3H), 7.41 (t, J=7.2 Hz, 2H), 7.68 (d, J=7.5 Hz, 2H), 7.89(d, J=7.5 Hz, 2H).

(S)-1-cyclopentyl-N-(4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:Diethylamine (0.28 mL, 2.7 mmol, 10 equiv.) was added to a solution of(S)-(9H-fluoren-9-yl)methyl(4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-yl)carbamate(135 mg, 0.266 mmol, 1.00 equiv.) in acetonitrile (2.7 mL). The reactionwas stirred for 1.5 h. The solvent was evaporated and the crude mixturewas co-evaporated 2× with DCM to provide 118 mg of the crude amine (64%w/w considering an hypothetic quantitative yield) which was used as is.HATU (16 mg, 0.041 mmol, 1.1 equiv.) was added to a solution of1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (12 mg, 0.037 mmol), HOAt (5.0 mg, 0.037 mmol, 1.0 equiv.) anddiisopropylethylamine (19 μL, 0.11 mmol, 3.0 equiv.) in DMF (0.2 mL). Asuspension of the crude amine (16 mg, 0.037 mmol, 1.0 equiv., 64% w/w)in DMF (0.17 mL) was added. The reaction mixture was stirred for 2 h.The reaction was put on top of a C-18 column and was purified by reversephase chromatography using a solution of MeCN in water (containing 10 mMof ammonium formate, pH=3.8) (5 to 65%). Fractions were combined andlyophilized to give 10 mg of the title compound which was furtherpurified by semi-prep HPLC-MS (column X-Bridge 30×50) using a solutionof MeCN in water (containing 10 mM of ammonium formate, pH=3.8) (45 to65%). Fractions were combined and lyophilized to provide 2.2 mg (10%) ofthe title compound. m/z (M+H)⁺=592.3; R_(T)=1.76 min; purity=>99%. HPLCconditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mMAmmonium Formate in Water; Eluent B: Acetonitrile. ¹H NMR (500 MHz,DMSO) δ 8.10 and 8.05 (d, J=8.6 Hz, 1H, NH, rotamers), 1.64-1.45 (m,4H), 1.73-1.65 (m, 1H), 2.10-1.76 (m, 10H), 2.22-2.12 (m, 2H), 2.84-2.73(m, 1H), 3.02-2.88 (m, 1H), 3.28-3.23 (m, 4H), 3.60-3.37 (m, 3H),3.91-3.68 (m, 3H), 4.20 (quint, J=7.4 Hz, 1H), 4.70-4.65 (m, 1H), 6.63(s, 1H), 7.57-7.51 (m, 2H), 7.76 (t, J=7.6 Hz, 1H), 7.82 (t, J=7.4 Hz,1H), 7.93 (d, J=8.0 Hz, 1H).

(S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoate:Cyclobutylamine (0.13 mL, 1.6 mmol, 2.5 equiv.) was added to a solutionof (S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(chlorosulfonyl)butanoate(275 mg, 0.628 mmol) in THF (3.1 mL). The reaction mixture was stirredfor 10 min and the solvent was evaporated. The crude product waspurified by flash chromatography on silica gel using a solution of ethylacetate in hexanes (5 to 60%) to provide 159 mg (54%) of the titlecompound as an orange viscous oil.m/z (M+H)⁺=473.1; R_(T)=1.72 min;purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A:pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. ¹H NMR(500 MHz, DMSO) δ 1.59-1.48 (m, 2H), 1.95-1.84 (m, 2H), 2.20-2.11 (m,2H), 2.58 (dd, J=15.7, 8.7 Hz, 1H), 2.76 (dd, J=15.7, 4.9 Hz, 1H), 3.10(dd, J=14.2, 6.5 Hz, 1H), 3.16 (dd, J=14.1, 6.3 Hz, 1H), 3.58 (s, 3H),3.70 (six, J=8.4 Hz, 1H), 4.25-4.18 (m, 2H), 4.34-4.26 (m, 2H),7.34-7.30 (m, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.54(d, J=8.7 Hz, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.89 (d, J=7.5 Hz, 2H).

(S)-3-(4(9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoicacid

HCl (conc., 0.84 mL) was added to a solution of (S)-methyl3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoate(140 mg, 0.335 mmol, 1.00 equiv.) in AcOH (8.4 mL). The reaction mixturewas heated at 100° C. for 15 h. The reaction mixture was poured in 70 mLof water and ethyl acetate was added. The phases were separated and theorganic layer was dried with sodium sulfate, filtered and evaporated.The crude mixture was co-evaporated with dioxane and DCM to provide 81mg (70%) of the title compound as a pale brown solid. m/z (M+H)⁺=459.2;R_(T)=1.64 min; purity=98.1%. HPLC conditions: Column: XBridge® C18, 3.5μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B:Acetonitrile.

(S)-(9H-fluoren-9-yl)methyl(1-(N-cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl)carbamate:HATU (74 mg, 0.19 mmol, 1.10 equiv.) was added to a solution of(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(N-cyclobutylsulfamoyl)butanoicacid (81 mg, 0.18 mmol, 1.0 equiv.), HOAt (24 mg, 0.18 mmol, 1.0equiv.), 3,3-difluoropiperidine hydrochloride (56 mg, 0.35 mmol, 2.0equiv.) and diisopropylethylamine (92 μL, 0.53 mmol, 3.0 equiv.) in DMF(0.7 mL) at 0° C. The reaction was stirred at rt for 3 days. Water wasadded, followed by ethyl acetate. The phases were separated and theorganic layer was washed with aq. satd. NaHCO₃ (3×), dried with sodiumsulfate, filtered and evaporated. The crude product was purified byflash chromatography on silica gel using a solution of MeOH in DCM (1 to2%) to provide 73 mg (74%) of the title compound as a pale orange solid.m/z (M+H)⁺=562.3; R_(T)=1.84 min; purity=99.2%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.59-1.48 (m, 3H),1.70-1.63 (m, 2H), 1.94-1.85 (m, 2H), 2.10-1.99 (m, 3H), 2.19-2.10 (m,2H), 2.74-2.66 (m, 1H), 3.18-3.12 (m, 1H), 3.47-3.41 (m, 1H), 3.83-3.65(m, 4H), 4.25-4.19 (m, 2H), 4.31-4.27 (m, 2H), 7.32 (t, J=7.5 Hz, 2H),7.41 (t, J=7.1 Hz, 2H), 7.51-7.47 (m, 1H), 7.68 (d, J=6.9 Hz, 2H), 7.89(d, J=7.6 Hz, 2H).

(S)—N-(1-(N-cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:Diethylamine (0.13 mL, 1.3 mmol, 10 equiv.) was added to a solution of(S)-(9H-fluoren-9-yl)methyl(1-(N-cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl)carbamate(73 mg, 0.13 mmol, 1.0 equiv.) in acetonitrile (1.3 mL). The reactionwas stirred for 1.5 h. The solvent was evaporated and the crude mixturewas co-evaporated 2× with DCM to provide 68 mg of the crude amine (65%w/w considering an hypothetic quantitative yield) which was used as is.HATU (17 mg, 0.046 mmol, 1.1 equiv.) was added to a solution of1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (14 mg, 0.042 mmol), HOAt (5.7 mg, 0.042 mmol, 1.0 equiv.) anddiisopropylethylamine (22 μL, 0.13 mmol, 3.0 equiv.) in DMF (0.22 mL). Asuspension of the crude amine (22 mg, 0.042 mmol, 1.0 equiv., 65% w/w)in DMF (0.20 mL) was added. The reaction mixture was stirred for 2 h.Water was added, followed by ethyl acetate. The phases were separatedand the organic layer was washed 2× with an aqueous saturated solutionof sodium bicarbonate, dried with sodium sulfate, filtered andevaporated. The crude product was purified by semi-prep HPLC-MS (columnX-Bridge 30×50) using a solution of MeCN in water (containing 10 mM ofammonium formate, pH=3.8) (55 to 75%). Pure fractions were combined andlyophilized to provide 6.7 mg (25%) of the title compound. m/z(M+H)⁺=646.3; R_(T)=1.93 min; purity=>99%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 8.15 and 8.11 (d, J=8.4Hz, 1H, NH, rotamers), 1.64-1.47 (m, 2H), 1.73-1.65 (m, 1H), 1.98-1.75(m, 4H), 2.11-1.99 (m, 2H), 2.89-2.77 (m, 1H), 3.04-2.92 (m, 1H),3.40-3.34 (m, 4H), 3.61-3.42 (m, 3H), 3.91-3.70 (m, 2H), 4.20 (quint,J=7.2 Hz, 1H), 4.77-4.68 (m, 1H), 6.62 (s, 1H), 6.99-6.94 (m, 2H), 7.54(d, J=7.8 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.93(d, J=7.5 Hz, 1H).

(R)-Benzyl-3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate: To astirred and cooled (−20° C., CryoCool) THF (150 mL) sol. ofBoc-D-Asp(βOBn)-OH (10.00 g, 30.93 mmol, 1.00 equiv.) under nitrogen wasadded N-methylmorpholine (3.40 mL, 30.93 mmol, 1.00 equiv.). Isobutylchloroformate (4.01 mL, 30.93 mmol, 1.00 equiv.) was next added over 45min. (syringe pump). The resulting white suspension was stirred 1 hr.Sodium borohydride (3.51 g, 92.79 mmol, 3.00 equiv.) was added in oneportion, mixture stirred in the cold 1 hr. Methanol (50 mL) was addeddrop-wise over c.a. 30 min. Mixture was stirred 30 min. then 40 mL ofaq. 1 M KHSO₄ was slowly added (over 30 min.), stirring continued 15min. then organic solvent was evaporated. Residue was treated with 30 mlof aq. 1M HCl and product was extracted 2×100 mL EtOAc. Organic extractswere pooled, washed with 25 mL aq. 1M HCl, 25 ml sat. aq. NaHCO₃, 25 mLwater, 25 ml sat. aq. NaCl. Sol. was dried (MgSO₄), filtered, filtrateevaporated. Residue was purified CombiFlash®, 100 g column, DCMisocratic 5 min. then to 10% MeOH/DCM in 15 min. Purest fractions werepooled, solvent evaporated, residue dried under high vacuum overnight toyield the title compound, 3.0 g (31%) clear thick oil. m/z(M+H)⁺−Boc=210.1; R_(T)=1.48 min; purity=80%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 2.37 (dd,J=15.3, 8.6 Hz, 1H), 2.60 (dd, J=15.2, 5.2 Hz, 1H), 3.25-3.18 (m, 1H),3.39-3.34 (m, 1H), 3.87-3.77 (m, 1H), 4.77 (t, J=5.7 Hz, 1H), 5.06 (s,2H), 6.67 (d, J=8.6 Hz, 1H), 7.38-7.30 (m, 5H).

(R)-Benzyl-3-((tert-butoxycarbonyl)amino)-4-(4-fluorophenoxy)butanoate:To a stirred, ice cold toluene (3 mL) solution of(R)-benzyl-3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (100 mg,0.320 mmol, 1.00 equiv.) under nitrogen was added p-fluorophenol (47 mg,0.420 mmol, 1.30 equiv.), triphenylphosphine (110 mg, 0.420 mmol, 1.30equiv.) and finally diamide (72 mg, 0.420 mmol, 1.30 equiv.). Suspensionwas stirred 1 hr in the cold, allowed to warm to RT, stirred overnight.Solvent was evaporated, residue purified CombiFlash®, 4 g column,dry-pack, 10% ethyl acetate/hexane isocratic 3 min. then to 50:50EtOAc:Hex in 15 min. Fractions containing product were pooled andsolvent was evaporated. Residue was still impure. It was re-purified,CombiFlash®, 12 g column, hexane, isocratic 4 min. then to 5% iPrOH/Hex.in 10 min. Purest fractions were pooled, solvent evaporated, residuedried under high vacuum to give the title compound, 62 mg (48%) as aclear oil. ¹H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 2.58 (dd, J=14.6, 8.0Hz, 1H),2.67 (dd, J=15.6, 5.9 Hz, 1H), 3.83 (dd, J=9.6, 6.2 Hz, 1H),3.92 (dd, J=9.6, 5.9 Hz, 1H), 5.09 (s, 2H), 4.23-4.12 (m, 1H), 6.95-6.87(m, 2H), 7.12-7.06 (m, 2H), 7.45-7.30 (m, 6H).

(R)-Benzyl3-amino-4-(4-fluorophenoxy)butanoate hydrochloride:(R)-benzyl-3-((tert-butoxycarbonyl)amino)-4-(4-fluorophenoxy)butanoate(60 mg, 0.15 mmol, 1.00 equiv.) was dissolved in 3 mL of HCl₄N/Dioxanesolution. Sol. was stirred at RT 2 hrs; nitrogen was bubbled in the sol.for 1 hr to remove as much HCl as possible. Solvent was evaporated; tothe oily residue was added 1 mL diethylether. Product was soluble;hexane (c.a. 0.5 mL) was slowly added to obtain a white precipitate.Suspension was sonicated 5 min. then centrifuged 10 min. at 3000 rpm,supernatant was decanted. Residual solid was re-suspended in 1.5 mLdiethylether, sonicated 10 min., centrifuged 10 min at 3000 rpm,supernatant was decanted, solid was dried under high vacuum to give thetitle compound, 36 mg (71%) as a white solid. m/z (M+H)⁺=304.0;R_(T)=1.32 min; purity=91.3%. HPLC conditions: Column: XBridge® C18, 3.5μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B:Acetonitrile.¹H NMR (500 MHz, DMSO) δ 2.89 (d, J=6.7 Hz, 2H), 3.90-3.82(m, 1H), 4.09 (dd, J=10.4, 6.2 Hz, 1H), 4.18 (dd, J=10.4, 3.8 Hz, 1H),5.16 (s, 2H), 7.01-6.95 (m, 2H), 7.18-7.12 (m, 2H), 7.41-7.32 (m, 5H),8.36 (s, broad, 3H).

(R)-Benzyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoate:To a stirred DMF (1 mL) sol. of1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (42 mg, 0.130 mmol, 1.25 equiv.) under nitrogen was added HATU (49mg, 0.130 mmol, 1.25 equiv.), HOAt (18 mg, 0.130 mmol, 1.25 equiv.) andDIPEA (72 μL, 0.412 mmol, 4.00 equiv.). Yellow sol. was stirred 10 min.then (R)-benzyl 3-amino-4-(4-fluorophenoxy)butanoate hydrochloride (32mg, 0.103 mmol, 1.00 equiv.) was added. Sol. was stirred 2 hrs at RT,diluted with EtOAc (20 ml), washed 2×10 ml aq. 0.5N citric acid, 3×10 mlsat. aq. NaHCO₃, 10 ml sat. aq. NaCl, dried (MgSO₄), filtered, filtrateevaporated. Residue was purified CombiFlash®, 12 g column, 10% EtOAc/Hexisocratic 3 min. then to 50% EtOAc/Hex in 10 min. Purest fractions werepooled, solvent evaporated, residue dried under high vacuum to give thetitle compound, 34 mg (61%) as a clear amorphous solid. m/z(M+H)⁺=610.4; R_(T)=2.17 min; purity=87.0%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.58-1.45 (m, 2H),2.05-1.72 (m, 6H), 2.91-2.83 (m, 2H), 4.03-3.97 (m, 1H), 4.25-4.07 (m,2H), 4.78-4.68 (m, 1H), 5.11 (s, 2H), 6.66 (s, 1H), 7.00-6.93 (m, 2H),7.14-7.07 (m, 2H), 7.35-7.25 (m, 5H), 7.54 (d, J=7.8 Hz, 1H), 7.77 (t,J=7.7 Hz, 1H), 7.83 (t, J=7.4 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 8.15 (d,J=8.7 Hz, 1H).

(R)-3-(1-Cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoicacid: To a stirred EtOAc (5 mL) sol. of (R)-benzyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoate(30 mg, 0.050 mmol, 1.00 equiv.) under nitrogen was added Pd/C 10% (25mg). System was purged 3×H₂ then hydrogenated (H₂ balloon) overnight.Mixture was filtered through Celite®, cake washed 3×10 mL EtOAc,filtrates pooled, solvent evaporated. Residue purified CombiFlash®, 12 gC₁₈ column, 1 min. isocratic aq. 10 mM ammonium bicarbonate then to 50%acetonitrile/ aq. 10 mM ammonium bicarbonate in 12 min. Purest fractionswere pooled, acetonitrile evaporated, remaining aq. sol. was frozen andlyophilized to give the title compound, 15 mg (58%) as a solid. .m/z(M+H)⁺=520.3; R_(T)=1.85 min; purity=92.2%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, CDCl₃) δ 1.60-1.46 (m, 2H),2.15-1.80 (m, 6H), 2.98-2.88 (m, 2H), 4.21-4.11 (m, 2H), 4.24 (dd,J=9.5, 4.0 Hz, 1H), 4.88-4.78 (m, 1H), 6.77 (s, 1H), 6.94-6.86 (m, 2H),6.98-6.95 (m, 2H), 7.30 (d, J=7.1 Hz, 1H), 7.65-7.57 (m, 3H), 7.67 (d,J=7.9 Hz, 1H), 7.80 (dd, J=7.4, 1.5 Hz, 1H).

(R)—N-(4-(Cyclobutylamino)-1-(4-fluorophenoxy)-4-oxobutan-2-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:To a stirred DMF (500 μL) sol. of(R)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-(4-fluorophenoxy)butanoicacid (12 mg, 0.023 mmol, 1.00 equiv.) under nitrogen was added HATU (13mg, 0.035 mmol, 1.50 equiv.), HOAt (4.8 mg, 0.035 mmol, 1.50 equiv.) andDIPEA (16 μL, 0.092 mmol, 4.00 equiv.). Yellow sol. was stirred 10 min.then cyclobutylamine (3.3 mg, 0.046 mmol, 2.00 equiv.) was added. Sol.was stirred 4 hrs at RT, diluted with EtOAc (20 ml), washed 2×10 ml aq.0.5N citric acid, 3×10 ml sat. aq. NaHCO₃, 10 ml sat. aq. NaCl, dried(MgSO₄), filtered, filtrate evaporated. Residue was purifiedCombiFlash®, 12 g column, DCM isocratic 2 min. to 2% MeOH/DCM in 6 min.Purest fractions were pooled, solvent evaporated, residue dried underhigh vacuum to give the title compound, 5.2 mg (40%) as a clearamorphous solid. m/z (M+H)⁺=573.4; R_(T)=1.95 min; purity=98.5%. HPLCconditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mMAmmonium Formate in Water; Eluent B: Acetonitrile. ¹H NMR (500 MHz,DMSO) δ 1.64-1.47 (m, 4H), 2.02-1.75 (m, 8H), 2.17-2.05 (m, 2H),2.52-2.45 (m, 1H), 2.55 (dd, J=14.6, 7.0 Hz, 1H), 3.98 (dd, J=9.9, 6.2Hz, 1H), 4.24-4.07 (m, 3H), 4.62-4.53 (m, 1H), 6.63 (s, 1H), 7.03-6.97(m, 2H), 7.14-7.08 (m, 2H), 7.53 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz,1H), 7.82 (t, J=7.5 Hz, 1H), 7.93 (d, J=7.3 Hz, 1H), 8.08 (d, J=8.4 Hz,1H), 8.21 (d, J=7.7 Hz, 1H).

(R)-benzyl3-((tert-butoxycarbonyl)amino)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate

HOBt (240 mg, 1.78 mmol, 1.15 equiv.) was added to a solution of(R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (500mg, 1.55 mmol) and tetrahydro-2H-pyran-4-amine (240 mg, 1.55 mmol) inDMF (10 mL). EDC.HCl(296 mg, 1.55 mmol) and N-methylmorpholine (202 mg,2.00 mmol) were added at 0° C. and the reaction mixture was stirred atrt for 15 h. Ethyl acetate was added and the mixture was washed with anaqueous saturated solution of sodium bicarbonate, with brine (2×), driedwith sodium sulfate, filtered and evaporated. The crude product waspurified by flash chromatography on silica gel using a solution of ethylacetate in hexanes (10 to 20%) to provide 488 mg (78%) of the titlecompound as a white solid. m/z (M+H)⁺=407.2; R_(T)=1.51 min;purity=>95%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A:pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile.

(R)-benzyl 3-amino-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoatehydrochloride:

4M HCl in dioxane (3.0 mL, 12 mmol) was added to (R)-benzyl3-((tert-butoxycarbonyl)amino)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate(488 mg, 1.20 mmol).The reaction was stirred at rt for 18 h. A saturatedaqueous solution of NaHCO₃ (25 mL) was added, followed by 6N NaOH untilpH=10. The mixture was extracted 4× with a solution of THF in DCM (1:3),the combined organic layers were dried with sodium sulfate, filtered andevaporated to provide 415 mg (quantitative yield) of the title compoundas a white foam. m/z (M+H)⁺=307.2; R_(T)=1.00 min; purity=>95%. HPLCconditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mMAmmonium Formate in Water; Eluent B: Acetonitrile.

(R)-benzyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate:

HATU (121 mg, 0.31 mmol) was added to a solution of1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (94 mg, 0.19 mmol), HOAt (39 mg, 0.29 mmol) anddiisopropylethylamine (150 μL, 0.87 mmol) in DMF (1 mL). The reactionmixture was stirred for 10 min and a solution of (R)-benzyl3-amino-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate hydrochloride(99 mg, 0.29 mmol)in DMF (0.85 mL) was added. The reaction mixture wasstirred at rt for 2 h. Water was added, followed by ethyl acetate. Thephases were separated and the organic layer was washed 2× with anaqueous saturated solution of sodium bicarbonate, dried with sodiumsulfate, filtered and evaporated. The crude product was purified byflash chromatography on silica gel using a solution of ethyl acetate inhexanes (20 to 40%) to provide 85 mg of the title compound as acolorless viscous oil. m/z (M+H)⁺=613.4; R_(T)=1.87 min; purity=99.5%.HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mMAmmonium Formate in Water; Eluent B: Acetonitrile.

(R)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoicacid:

10% Pd/C (10 mg) was added to a nitrogen purged flask containing asolution of (R)-benzyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate(85 mg (0.14 mmol) in EtOH (0.5 mL). The flask was put under vacuum for30 sec and put back under nitrogen. This procedure was done anothertime. The flask was put back again under vacuum and a balloon ofhydrogen was inserted through the septum. The reaction was vigorouslystirred for 15 h. The flask was put under vacuum for 30 sec and put backunder nitrogen. This procedure was done two other times. The solutionwas filtered on Celite®, the solid cake was washed with EtOH and thefiltrate was evaporated to provide 61 mg (85%) of the title compound asa white solid. Half the compound was dissolved in a mixture ofacetonitrile and water and was lyophilized to give 23 mg of a whitesolid. m/z (M+H)⁺=523.2; R_(T)=1.51 min; purity=99.1%. HPLC conditions:Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formatein Water; Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.48-1.36 (m,2H), 1.58-1.48 (m, 2H), 1.71-1.63 (m, 2H), 1.90-1.77 (m, 3H), 2.01-1.90(m, 3H), 2.78-2.66 (m, 2H), 3.38-3.33 (m, 2H), 3.85-3.70 (m, 3H), 4.21(quint, J=7.4 Hz, 1H), 4.76-4.69 (m, 1H), 6.66 (s, 1H), 7.54 (d, J=7.5Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.94 (d, J=7.6Hz, 1H), 8.14-8.00 (m, 2H), 12.43-12.22 (m, 1H).

(S)-5-((3-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)amino)pentanoicacid: To a stirred methanol (2 mL) sol. of 5-aminovaleric acid (38 mg,0.372 mmol, 1.20 equiv.) under nitrogen was added (S)-tert-butyl3-(((benzyloxy)carbonyl)amino)-5-oxopentanoate (100 mg, 0.310 mmol) in 1mL methanol. Sol. was stirred at RT 1 hr then sodiumtriacetoxyborohydride (79 mg, 0.372 mmol, 1.2 equiv.) was added. Sol.was stirred a further hour, solvent evaporated, residue purifiedCombiFlash®, 30 g column (C18), 10 mM aq. ammonium formate isocratic 5min. then to 50% aq. AF-acetonitrile in 10 min., isocratic 8 min. thento 100% acetonitrile in 10 min. Purest fractions were pooled, solventsevaporated (rotavapor, 45° C., high vacuum), residue re-dissolved inethanol (30 mL), solvent re-evaporated, residue dried under high vacuumto give the title compound, 59 mg (45%) amorphous solid. m/z(M+H)⁺=423.4; R_(T)=1.28 min; purity=92.7%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 1.70-1.42(m, 6H), 2.16 (t, J=6.7 Hz, 2H), 2.40-2.30 (m, 2H), 2.65-2.54 (m, 3H),4.40-3.20 (m, 4H), 5.05-4.97 (m, 2H), 7.38-7.25 (m, 5H), 8.37 (s, boad,1H).

(S)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-5-(2-oxopiperidin-1-yl)pentanoate:To a stirred DMF (500 μL) sol. of(S)-5-((3-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)amino)pentanoicacid (55 mg, 0.130 mmol, 1.00 equiv.) under nitrogen was added DIPEA (90μL, 0.520 mmol, 4.00 equiv.) followed by HOAt (28 mg, 0.208 mmol, 1.60equiv.) and HATU (74 mg, 0.195 mmol, 1.50 equiv.). Yellow sol. wasstirred at RT 1 hr, diluted with EtOAc (20 mL), washed 4×10 mL sat. aq.NaHCO₃, 2×10 mL sat. aq. NaCl, dried (MgSO₄), filtered, filtrateevaporated. Crude material was used as such for next transformation. m/z(M+H)⁺=405.2; R_(T)=1.57 min; purity: 69%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B -100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.36 (s, 9H), 1.73-1.50(m, 6H), 2.20-2.12 (m, 2H), 2.38-2.27 (m, 2H), 3.31-3.12 (m, 4H),3.82-3.74 (m, 1H), 5.07-4.95 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 7.38-7.28(m, 5H).

(S)-tert-butyl-3-amino-5-(2-oxopiperidin-1-yl)pentanoate: To a stirredEtOAc (5 mL) sol. of(S)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-5-(2-oxopiperidin-1-yl)pentanoate(25 mg, 0.062 mmol, 1.00 equiv.) under nitrogen was added Pd/C 10% (50mg). System was purged 3× with H₂ then hydrogenated (balloon) 4 hrs.Mixture was filtered over Celite® (under a nitrogen stream), cake washed4×10 mL EtOAc, all filtrates pooled, solvent evaporated. Residue driedunder high vacuum overnight to give the title compound, 6.8 mg (41%) asa glassy solid. Crude material was used as such for next transformation.

(S)-tert-butyl-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2-oxopiperidin-1-yl)pentanoate:To a stirred DMF (1 mL) sol. of1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (9.4 mg, 0.029 mmol, 1.20 equiv.) under nitrogen was added HATU (11mg, 0.030 mmol, 1.25 equiv.), HOAt (4 mg, 0.030 mmol, 1.25 equiv.) andDIPEA (17 μL, 0.096 mmol, 4.00 equiv.). Yellow sol. was stirred 5 min.then (S)-tert-butyl 3-amino-5-(2-oxopiperidin-1-yl)pentanoate (6.8 mg,0.024 mmol, 1.00 equiv.) was added. Sol. was stirred 3 hrs at RT,diluted with EtOAc (20 ml), washed 4×10 ml sat. aq. NaHCO₃, 10 ml sat.aq. NaCl, dried (MgSO₄), filtered, filtrate evaporated. Residue waspurified CombiFlash®, 4 g column, isocratic DCM 1 min. then to 5%MeOH/DCM in 12 min. Purest fractions were pooled, solvent evaporated,residue dried overnight under high vacuum to give the title compound,9.4 mg (68%) amorphous solid. m/z (M+H)⁺=577.4; R_(T)=1.90 min; purity :98%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient:5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10mM Ammonium Formate in Water; Eluent B: Acetonitrile. ¹H NMR (500 MHz,CDCl₃) δ 1.45 (s, 9H), 2.20-1.65 (m, 12H), 2.40-2.28 (m, 2H), 2.70-2.58(m, 2H), 3.46-3.17 (m, 3H), 3.77-3.47 (m, 1H), 1.60-1.48 (m, 2H),4.22-4.10 (m, 1H), 4.43-4.34 (m, 1H), 6.74 (s, 1H), 7.31 (d, J=7.2 Hz,1H), 7.43-7.37 (m, 1H), 7.66-7.56 (m, 2H), 7.80 (dd, J=7.9, 1.0 Hz, 1H).

(S)-tert-butyl-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,5-dimethyl-1H-pyrazol-1-yl)pentanoate:(S)-tert-butyl-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2-oxopiperidin-1-yl)pentanoate(9.0 mg, 0.016 mmol, 1.00 equiv.) was dissolved in 4N HCl/dioxane (2 mL)solution and stirred at RT 3 hrs. Solvent was evaporated, residue driedunder high vacuum. Residue was purified CombiFlash®, 12g C18 column, 1min. isocratic aq. 10 mM ammonium bicarbonate then to 50%acetonitrile/aq. 10 mM ammonium bicarbonate in 12 min. Purest fractionswere pooled, acetonitrile evaporated, remaining aq. sol. was frozen andlyophilized to give the title compound, 8.0 mg (96%).m/z (M+H)⁺=521.3;R_(T)=1.55 min; purity : 96%. HPLC conditions: Column: XBridge® C18, 3.5μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water; Eluent B:Acetonitrile. ¹H NMR (500 MHz, DMSO) δ 1.53-1.46 (m, 2H), 2.03-1.60 (m,10H), 2.19-2.13 (m, 2H), 2.63-2.46 (m, 4H), 3.75-3.15 (m, 4H), 4.30-4.15(m, 2H), 6.62 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H),7.82 (t, J=7.4 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.98-7.90 (m, broad,1H), 12.40-12.00 (s, broad, 1H).

(S)-tert-butyl3-(((benzyloxy)carbonyl)amino)-5-(2,6-dioxopiperidin-1-yl)pentanoate

A solution of ADDP (41 mg, 0.16 mmol, 1.3 equiv.) in THF (0.6 mL) wasadded to a solution of (S)-tert-butyl3-(((benzyloxy)carbonyl)amino)-5-hydroxypentanoate (40 mg, 0.12 mmol,1.0 equiv.), glutarimide (14 mg, 0.12 mmol, 1.0 equiv.),diisopropylethylamine (24 μL, 0.14 mmol, 1.1 equiv.) andtributylphosphine (40 μL, 0.16 mmol, 1.3 equiv.) in THF (0.64 mL). Thereaction mixture was stirred at rt for 16 h and was filtered in apipette with a cotton wool. Water was added to the filtrate and themixture was extracted with ethyl acetate (2×). The combined organiclayers were dried with sodium sulfate filtered and evaporated. The crudeproduct was purified by flash chromatography on silica gel using asolution of ethyl acetate in hexanes (30 to 60%) to provide 34 mg (66%)of the title compound as a pale yellow oil. m/z (M+H)⁺=419.3; R_(T)=1.62min; purity=>90%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. EluentA: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. ¹HNMR (500 MHz, CDCl₃) δ 7.37-7.28 (m, 5H), 5.35 (d, J=8.5 Hz, 1H),5.15-5.03 (m, 2H), 3.95-3.79 (m, 3H), 2.66-2.57 (m, 4H), 2.51-2.44 (m,2H), 1.96-1.87 (m, 2H), 1.83-1.71 (m, 2H), 1.43 (s, 9H).

(S)-tert-butyl 3-amino-5-(2,6-dioxopiperidin-1-yl)pentanoate

10% Pd/C (10 mg) was added to a nitrogen purged flask containing asolution of (S)-tert-butyl3-(((benzyloxy)carbonyl)amino)-5-(2,6-dioxopiperidin-1-yl)pentanoate (34mg, 0.081 mmol, 1.00 equiv.) in EtOH (0.27 mL). The flask was put undervacuum for 30 sec and put back under nitrogen. This procedure was doneanother time. The flask was put back again under vacuum and a balloon ofhydrogen was inserted through the septum. The reaction was vigorouslystirred for 18 h. The flask was put under vacuum for 30 sec and put backunder nitrogen. This procedure was done two other times. The solutionwas filtered on Celite®, the solid cake was washed with EtOH and thefiltrate was evaporated. The obtained product (23 mg) was resubmitted tothe above reaction, using ethyl acetate as the solvent this time, toprovide 7.5 mg (32%) of the title compound as a colorless oil. m/z(M+H)⁺=285.3; R_(T)=1.08 min; purity=77.8%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: Acetonitrile.

(S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2,6-dioxopiperidin-1-yl)pentanoate

HATU (7.1 mg, 0.019 mmol, 1.1 equiv.) was added to a solution of1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (5.5 mg, 0.017 mmol, 1.0 equiv.), HOAt (2.3 mg, 0.017 mmol, 1.0equiv.) and diisopropylethylamine (8.9μL, 0.051 mmol, 3.0 equiv.) and(S)-tert-butyl 3-amino-5-(2,6-dioxopiperidin-1-yl)pentanoate (7.5 mg,0.017 mmol, 1.0 equiv.) in DMF (0.17 mL) at 0° C. The reaction mixturewas stirred at rt for 18 h. The mixture was dissolved in ethyl acetateand was washed with a saturated aqueous solution of sodium bicarbonate,dried with sodium sulfate, filtered and evaporated to provide 6.5 mg(65%, crude) of the title compound which was used as is. m/z(M+H)⁺=591.3; R_(T)=1.93 min; purity=hard to say. HPLC conditions:Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formatein Water; Eluent B: Acetonitrile.

(S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2,6-dioxopiperidin-1-yl)pentanoicacid

A 4M solution of HCl in dioxane (0.28 mL, 1.1 mmol, 100 equiv.) wasadded to crude (S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(2,6-dioxopiperidin-1-yl)pentanoate(6.5 mg, 0.011 mmol, 1.00 equiv.). The reaction mixture was stirred atrt for 18 h and the solvent was evaporated. The crude product waspurified by semi-prep HPLC-MS (column X-Bridge 30×50) using a solutionof MeCN in water (containing 10 mM of ammonium formate, pH=3.8) (40 to60%). Pure fractions were lyophilized to provide 0.65 mg (11%) of thetitle compound as a white solid. m/z (M+H)⁺=535.3; R_(T)=1.60 min;purity=>99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B -100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A:pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. ¹H NMR(500 MHz, CD₃CN) δ 7.88 (d, J=7.3 Hz, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.69(t, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 6.64 (s, 1H), 4.32-4.22 (m, 2H),3.80-3.71 (m, 2H), 2.68-2.61 (m, 1H), 2.61-2.51 (m, 1H), 2.54 (t, J=6.7Hz, 4H), 2.10-2.05 (m, 2H), 1.96-1.92 (m, 2H), 1.88-1.77 (m, 6H),1.59-1.51 (m, 2H).

(3S)-tert-butyl-3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)-2-methylpentanoate:To a stirred THF (10 mL) sol. of freshly distilled (over CaH₂)diisopropylamine (651 μL, 4.64 mmol, 2.20 equiv.) at −78° C. undernitrogen was added drop-wise n-BuLi 2.46 M/Hexane (1.80 mL, 4.43 mmol,2.10 equiv.). Resulting sol. was stirred 1 hr at −78° C., (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)pentanoate (1.00 g, 2.11mmol, 1.00 equiv.) dissolved in THF (2 mL) was added drop-wise, sol. wasstirred 2 hrs at −78° C. Iodomethane (525 μL, 8.44 mmol, 4.00 equiv.)was added drop-wise, sol. stirred 4 hrs at −78° C., stirring wascontinued overnight, temperature rose to c.a. −10° C. during thisperiod. Reaction was quenched by the addition of 1 ml sat. aq. NH₄C₁,stirred 15 min, THF was evaporated, residue parted between sat. aq.NaHCO₃ (50 ml) and EtOAc (50 ml). Organic layer was washed 50 ml sat.aq. NaHCO_(3, 50) mL sat. aq. NaCl, dried (MgSO₄), filtered, filtrateevaporated, residue dried under high vacuum to give the title compound,953 mg (92%) thick amber oil.m/z (M+H)⁺=488.3; R_(T)=2.44 min; purity :93%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient:5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A: pH 3.8 10mM Ammonium Formate in Water; Eluent B: Acetonitrile. ¹H NMR (500 MHz,DMSO, mixture of conformers/rotamers) δ 7.40-7.15 (m, 15H), 4.47-4.36(m, 2H), 3.95-3.63 (m, 3H), 3.55-3.35 (m, 2H), 3.27-3.22 (m, 0.5H),2.88-2.83 (m, 0.5H), 2.36-2.25 (m, 1H), 1.88-1.75 (m, 1H), 1.70-1.60 (m,1H), 1.31; 1.32 (2s, 9H), 1.25-1.20 (m, 3H), 0.82-0.76 (m, 3H).

(3S)-tert-butyl-3-amino-5-hydroxy-2-methylpentanoate: In a Parr shakerreactor(3S)-tert-butyl-3-(benzyl((S)-1-phenylethyl)amino)-5-(benzyloxy)-2-methylpentanoate(950 mg, 1.95 mmol, 1.00 equiv.) was dissolved in 20% AcOH/Ethanol (50ml). Vessel was purged with nitrogen then Pd/C 10% (600 mg) was added.System was evacuated (house vacuum), filled with hydrogen (45 psi),shaken 5 min. System was purged a second time then put under hydrogenpressure (50 psi) and shaken for 30 hrs. System was purged 2× nitrogen,mixture was filtered through a Celite® cake, washed 4×10 ml ethanol,filterate and washings were pooled and evaporated (rotavapor, highvacuum) to give the title compound, 403 mg, which was used as such forthe next transformation.

(3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxy-2-methylpentanoate:1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicacid (159 mg, 0.49 mmol) was gently refluxed in thionyl chloride (4 mL)under nitrogen for 4 hrs. Volatiles were evaporated, residuere-dissolved in 4 mL dioxane, solvent evaporated, solid dried under highvacuum 1 hr. This solid was dissolved in THF, DIPEA (257 μL, 1.48 mmol,3.00 equiv.) was added drop-wise followed by (3S)-tert-butyl3-amino-5-hydroxy-2-methylpentanoate (100 mg, 0.49 mmol)dissolved-suspended in THF (1 mL). Resulting sol. turned to whitesuspension shortly after addition. Stirred under nitrogen 2 hrs, dilutedwith EtOAc (40 ml), washed 3×20 ml sat. aq. NaHCO_(3, 20) ml sat. aq.NaCl, dried (MgSO₄), filtered, filtrate evaporated. Product purifiedCombiFlash®, dry-pack, 10 g column, 20% EtOAc isocratic 2 min. then to50% EtOAc/Hex. in 6 min, isocratic 2 min. Purest fractions were pooled,solvent evaporated, residue dried under high vacuum to to give the titlecompound, 83 mg (33%) as an amorphous solid.m/z (M+H)⁺=510.4; R_(T)=1.96min; purity : 99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. EluentA: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: Acetonitrile. ¹HNMR (500 MHz, DMSO) δ 1.09-1.02 (m, 3H), 1.38 (s, 1H), broad (9H), 1.42(s, 1H), 1.58-1.46 (m, 2H), 1.73-1.63 (m, 2H), 2.05-1.75 (m, 6H),2.73-2.60 (m, 1H), 3.48-3.36 (m, 2H), 4.25-4.10 (m, 2H), 4.50-4.44 (m,2H), 6.63 (d, J=6.2 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz,1H), 7.82 (t, J=7.3 Hz, 1H), 7.82 (t, J=7.3 Hz, 1H), 7.82 (t, J=7.3 Hz,1H).

(3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-2-methyl-5-oxopentanoate:To a stirred, ice cold DCM (2 mL) sol. of (3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxy-2-methylpentanoate(80 mg, 0.157 mmol) under nitrogen was added Dess-Martin periodinane(100 mg, 0.236 mmol, 1.5 equiv.). The white suspension was stirred 15min. in the cold, allowed to warm to RT and stirred overnight. Mixturewas diluted with EtOAc (40 mL) washed 4×25 ml sat. aq. NaHCO₃, 25 mlsat. aq. NaCl, dried (MgSO₄), filtered, filtrate was evaporated, residuedried under high vacuum 1 hr. Crude material was used as such for nexttransformation.

(3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoate(A and B)

To a stirred methanol (2 mL) sol. of 3,3-difluoropyrollidinehydrochloride (42 mg, 0.268 mmol, 1.00 equiv.) under nitrogen was addedtriethylamine (50 μL, 0.358 mmol, 3.00 equiv.). Sol. was stirred 15 min.then (3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-2-methyl-5-oxopentanoate(60 mg, 0.118 mmol, 1.00 equiv.) in 1 mL methanol was added. Sol. wasstirred at RT 1 h then sodium triacetoxyborohydride (45 mg, 0.215 mmol,1.80 equiv.) was added. Solution was stirred a further 3 hrs, solventwas evaporated, residue taken in ethyl acetate (30 mL), washed 3×20 mLsat. aq. NaHCO₃, 20 mL sat. aq. NaCl, dried (MgSO₄), filtered, filtrateevaporated. Residue purified CombiFlash®, 12 g column, DCM isocratic 3min. then to 1% MeOH/DCM in 6 min. isocratic 5 min. Two products wereseparated;

(3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoateA (less polar diastereomer), 17.6 mg (24%) amorphous solid [49% based ona 1:1 mixture of diastereoisomers].

m/z (M+H)⁺=614.5; R_(T)=2.12 min; purity : 95%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm; Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate in Water;Eluent B: CH₃CN. ¹H NMR (500 MHz, CDCl₃) δ 1.21 (d, J=7.1 Hz, 3H), 1.48(s, 9H), 1.58-1.49 (m, 2H), 2.20-1.61 (m, 12H), 2.79-2.37 (m, 7H), 4.16(p, J=7.6 Hz, 1H), 4.35-4.26 (m, 1H), 6.75 (s, 1H), 7.28 (d, broad,J=9.8 Hz, 1H), 7.32 (d, broad, J=7.1 Hz, 1H), 7.65-7.56 (m, 2H), 7.80(dd, J=7.8, 1.0 Hz, 1H).

(3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoateB (more polar diastereomer), 23.5 mg (33%) amorphous solid [65% based ona 1:1 mixture of diastereoisomers].

m/z (M+H)⁺=614.5; R_(T)=2.12 min; purity : 93%. HPLC conditions: Column:XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B-100B 1.8 min,100B 1 min; 3 mL/min. Eluent A: pH 3.8 10 mM Ammonium Formate inWater;Eluent B: CH₃CN. ¹H NMR (500 MHz, CDCl₃) δ 1.22 (d, J=6.1 Hz, 3H),1.48 (s, 9H), 1.55-1.50 (m, 2H), 2.17-1.70 (m, 12H), 2.74-2.37 (m, 7H),4.21-4.12 (m, 1H), 4.32-4.23 (m, 1H), 6.74 (s, 1H), 7.32 (d, J=7.2 Hz,1H), 7.56-7.45 (m, 1H), 7.65-7.57 (m, 2H), 7.80 (d, J=7.2 Hz, 1H).

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoicacid (Acid 1): (3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoateA (16 mg, 0.026 mmol, 1.00 equiv.) was dissolved in 4NHCl/dioxanesolution (4 mL). Stirred at RT 4 hrs, volatiles were evaporated, residuepurified CombiFlash®, 12 g Biotage KP-C18-HS column, aq. 10 mM ammoniumbicarbonate isocratic 1 min., to 50% acetonitrile in 5 min., isocratic 3min. Purest fractions were pooled, most acetonitrile was evaporated,remaining solution was frozen and lyophilized to give the titlecompound, 7.5 mg (52%) white solid.m/z (M+H)⁺=557.3; R_(T)=1.54 min;purity : 98%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30 mm;Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. Eluent A:pH 3.8 10 mM Ammonium Formate in Water; Eluent B: CH₃CN. ¹H NMR (500MHz, DMSO) δ 1.06 (d, J=7.0 Hz, 3H), 1.56-1.45 (m, 2H), 1.73-1.57 (m,4H), 2.05-1.75 (m, 8H), 2.44-2.30 (m, 4H), 2.65-2.55 (m, 3H), 4.23-4.09(m, 2H), 6.63 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H),7.82 (t, J=7.4 Hz, 1H), 7.88-7.79 (s, broad, 1H), 7.93 (d, J=7.4 Hz,1H), 11.70 (s, broad, 1H).

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoicacid (Acid 2): (3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoateB(22 mg, 0.036 mmol, 1.00 equiv.) was dissolved in 4N HCl/dioxanesolution (4 mL). Stirred at RT 4 hrs, volatiles were evaporated, residuepurified CombiFlash®, 12 g Biotage KP-C18-HS column, aq. 10 mM ammoniumbicarbonate isocratic 1 min., to 40% acetonitrile in 5 min., isocratic 4min. Purest fractions were pooled, most acetonitrile was evaporated,remaining solution was frozen and lyophilized to give the titlecompound, 14.6 mg (73%) white solid.m/z (M+H)⁺=557.2; R_(T)=1.56 min;purity : >99%. HPLC conditions: Column: XBridge® C18, 3.5 μm, 4.6×30mm;Gradient: 5B 0.2 min, 5B-100B 1.8 min, 100B 1 min; 3 mL/min. EluentA: pH 3.8 10 mM Ammonium Formate in Water; Eluent B: CH₃CN. ¹H NMR (500MHz, DMSO) δ 13.20-11.80 (s, broad, 1H), 1.09 (d, J=7.1 Hz, 3H),1.56-1.45 (m, 2H), 1.75-1.58 (m, 4H), 2.00-1.75 (m, 8H), 2.45-2.32 (m,4H), 2.73-2.55 (m, 3H), 4.15-4.05 (m, 1H), 4.20 (p, J=7.2 Hz, 1H), 6.62(s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (t, J=7.4Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 8.13-7.92 (s, broad, 1H)

(3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxyhexanoate:To a solution of (S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxopentanoate(230mg, 0.466 mmol) in THF (10 mL) at −78° C. was slowly added a solution ofCH₃MgBr (0.31 mL, 0.93 mmol, 3.0 M in Et₂O). The mixture was allowed tostir at −78° C. for 30 min. Then the solution was warmed to rt andstirring for 4 h. The reaction was quenched with water (2 mL). Then thesolution was extracted with Et₂O (3×15 mL), the combined organic layerswere dried over MgSO₄, concentrated in vacuo and purified bychromatography over silica gel, eluting with 0-40% EtOAc/Hexanes to giveknown (3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxyhexanoate,yield 85% colorless oil. ¹H NMR (300 MHz, CDCl₃) δ1.23-1.29 (m, 3H),1.39-1.61 (m, 11H), 1.80-2.16 (m, 8H), 2.58-2.74 (m, 2H), 3.91-4.05 (m,1H), 4.08-4.25 (m, 1H), 4.43-4.68 (m, 1H), 6.73-6.79 (m, 1H), 7.29-7.37(m, 1H), 7.49-7.70 (m, 3H), 7.76-7.87 (m, 1H).LC-MS (ESI): m/z [M+H⁺]510.5.

(S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxohexanoate:To a solution of crude (3S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-hydroxyhexanoate(100 mg 0.196 mmol) in DCM (6 mL) was added sodium bicarbonate (33 mg,0.39 mmol) followed by Dess Martins reagent (166 mg, 0.39 mmol). Themixture was allowed to stir for overnight before the reaction wasquenched with 10% aqueous sodium bicarbonate (2 mL). Then the solutionwas extracted with Et₂O (3×15 mL), the combined organic layers weredried over MgSO₄, concentrated in vacuo and purified by chromatographyover silica gel, eluting with 0-40% EtOAc/Hexanes to give known ketone(S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxohexanoate,yield 85% colorless oil. ¹H NMR (300 MHz, CDCl₃) δ1.45 (s, 9H),1.78-2.04 (m, 8H), 1.50-1.61 (m, 2H), 2.20 (s, 3H), 2.66-2.76 (m, 2H),2.90-3.10 (m, 2H), 4.08-4.23 (m, 1H), 4.65-4.82 (m, 1H), 6.74 (s, 1H),7.28-7.36 (m, 1H), 7.51-7.67 (m, 3H), 7.76-7.84 (m, 1H).LC-MS (ESI): m/z[M+H⁺] 508.5.

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (A and B): A solution of the ketone (S)-tert-butyl3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-oxohexanoate(75mg, 0.147 mmol), 3,3 difluoro piperidine hydrochloride (28 mg, 0.177mmol), crushed 4 A molecular sieves in dichloroethane (10 mL) wastreated with sodium triacetoxyborohydride (63 mg 0.294 mmol) and theresulting mixture was stirred at ambient temperature overnight. Thesieves were filtered off through a plug of Celite®, the filtrate waswashed with a saturated solution of sodium bicarbonate, water and brine.The combined aqueous solutions were back extracted with dichloromethane,the combined organic extracts were dried with anhydrous sodium sulfate,and the solvent was evaporated in vacuo and purified by chromatographyover silica gel, eluting with 0-35% EtOAc/Hexanes to give the twodiastereoisomers (A and B).

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid(A, less polar diastereomer), yield 20 mg (30%) colorless oil. ¹HNMR (300 MHz, CDCl₃) δ 1.02 (d, J=6.59 Hz, 3H), 1.47 (s., 9H), 1.50-1.61(m, 2H), 1.69-2.05 (m, 12H), 2.31-2.46 (m, 1H), 2.55-2.71 (m, 4H),2.72-2.92 (m, 2H), 4.10-4.23 (m, 1H), 4.45-4.60 (m, 1H), 6.75 (s, 1H),7.30-7.43 (m, 1H), 7.56-7.67 (m, 3H), 7.77-7.83 (m, 1H).LC-MS (ESI): m/z[M+H⁺] 613.7.

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (B, more polar diastereomer), yield 6.5 mg (10%) colorless oil. ¹HNMR (300 MHz, CDCl₃) δ 0.98 (d, J=6.59 Hz, 3H), 1.45 (s, 9H), 1.50-1.61(m, 2H), 1.67-2.18 (m, 12H), 2.31-2.46 (m, 1H), 2.61-2.95 (m, 6H),4.04-4.22 (m, 1H), 4.44-4.58 (m, 1H), 6.75 (s, 1H), 7.28-7.35 (m, 1H),7.51-7.68 (m, 3H), 7.77-7.84 (m, 1H). LC-MS (ESI): m/z [M+H⁺] 613.8.

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (Acid 1): To a solution of(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (A)(20 mg) in DCM:TFA (1:1, 1 mL) and stirred at rt for 2 h.Solvent was removed in vacuo and diluted with CHCl₃. Solvent was removedto provide 90%(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (Acid 1) as a white solid,. ¹H NMR (300 MHz, CDCl₃) δ1.40-1.56 (m,6H), 1.77-2.21 (m, 12H), 2.43-2.63 (m, 1H), 2.70-2.81 (m, 2H), 3.2-3.93(m, 4H), 4.07-4.24 (m, 1H), 4.45-4.65 (m, 1H), 6.74 (s, 1H), 7.37-7.28(m, 1H), 7.62 (t, J=6.40 Hz, 2H), 7.81 (d, J=8.48 Hz, 1H), 7.85-7.98 (m,1H).LC-MS (ESI): m/z[M+H⁺] 557.9, [M−H⁺] 556.0.

(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (Acid 2): To a solution of(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid (B)(6 mg) in DCM:TFA (1:1, 1 mL) and stirred at rt for 2 h. Solventwas removed in vacuo and diluted with CH₂Cl₂. Solvent was removed toprovide 90% of(3S)-3-(1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)hexanoicacid(Acid 2)as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.32-1.58 (m,6H), 1.78-2.43 (m, 12H), 2.80-2.95 (m, 2H), 3.04-3.61 (m, 4H), 4.16 (d,J=6.97 Hz, 1H), 4.25-4.44 (m, 1H), 6.74 (br. s., 1H), 7.28-7.37 (m, 1H),7.63 (t, J=6.12 Hz, 2H), 7.81 (d, J=7.91 Hz, 1H), 8.02-8.23 (m,1H).LC-MS (ESI): m/z [M+H⁺] 557.9, [M−H⁺] 556.1.

Ethyl1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate:To a solution of 85 (0.90 g, 4.0 mmol) in Et₂O (40 ml) at −78° C. wasadded dropwise of nBuLi (1.9 ml, 2.5 M in hexanes, 4.8 mmol). Afteraddition the mixture was stirred at −78° C. for 1 h, followed bydropwise addition of Bu₃SnC₁ (1.20 ml, 4.4 mmol). Stirring was continuedat this temperature for 1 h and then slowly warmed to rt. The solutionwas quenched with ammonium chloride (sat., 20 ml) and extracted withhexanes (20 ml). The extract was dried (Na₂SO₄) and concentrated. Theconcentrate was triturated with hexanes, filtered and concentrated togive a brown oil (1.51 g).

To a mixture of the above oil (0.79 g), bromopyrazole (0.43 g, 1.5 mmol)and toluene (15 ml) in a sealed tube was added Pd(PPh₃)₂Cl₂ (53 mg,0.075 mmol) under N₂. The mixture was heated at 120° C. for 40 h. Thenit was concentrated and purified using EA in hexanes to give the desiredproduct 86 (50 mg) as a yellow oil; ¹H NMR (200 MHz, CDCl₃): δ=1.39 (t,3H, J=7.4 Hz), 1.40-1.70 (m, 2H), 1.80-2.30 (m, 6H), 4.30-4.50 (m, 3H),6.91 (s, 1H), 7.40-7.60 (m, 1H), 8.17 (d, 1H, J=8.0 Hz), 8.93 (d, 1H,J=4.6 Hz); LC-MS (ESI): m/z calculated for C₁₇H₂₀F₃N₃O₂ [M+H⁺]: 354,Found: 354.0.

1-Cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylicacid: To a solution of ethyl1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate(50 mg, 0. 141 mmol) in THF (5 ml) and H₂O (1 ml) was added LiOH (10mg). The mixture was stirred at rt for 20 h, acidified to PH 4, andextracted with EtOAc. The EtOAc extract was dried (Na₂SO₄), concentratedand purified (if necessary) to give title compound (45 mg) as a brownsolid; ¹H NMR (200 MHz, CDCl₃): δ=1.40-1.70 (m, 2H), 1.80-2.30 (m, 6H),4.40-4.60 (m, 1H), 6.99 (s, 1H), 7.50-7.60 (m, 1H), 8.17 (d, 1H, J=8.0Hz), 8.93 (d, 1H, J=4.4 Hz); LC-MS (ESI): m/z calculated forC₁₅H₁₆F₃N₃O₂ [M+H⁺]: 326, Found: 325.9.

(S)-Tert-butyl3-(1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate:A mixture of1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylicacid(42 mg, 0.15 mmol), (S)-tert-butyl3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate(67 mg, 0.23 mmol), Et₃N(0.060 ml, 0.60 mmol) and TBTU (72 mg, 0.22) in MeCN (5 ml) was stirredat rt for 15 h. The mixture was diluted with EtOAc and washed withNaHCO₃. The organic layer was dried (Na₂SO₄), concentrated, and purifiedusing 0-10% MeOH in DCM (with 1% NH₃) to give the title compound (58 mg)as a colorless oil; ¹H NMR (200 MHz, CDCl₃): δ=1.40 (s, 9H), 1.50-2.20(m, 14H), 2.30-2.80 (m, 8H), 4.30-4.60 (m, 2H), 6.61 (d, 1H, J=9.8 Hz),6.89 (s, 1H), 7.40-7.60 (m, 1H), 8.13 (d, 1H, J=8.0 Hz), 8.91 (d, 1H,J=4.0 Hz); LC-MS (ESI): m/z calculated for C₂₉H₃₉F₅N₅O₃ [M+H⁺]: 600,Found: 599.8.

(S)-3-(1-Cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid: To a solution of (S)-tert-butyl3-(1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoate(50 mg) in DCM (2 ml) was added HCl (4 M in dioxane, 0.1 ml). Themixture was stirred at rt for 15 h and concentrated to dryness to givethe acid as the HCl salt. (40 mg). LC-MS (ESI): m/z calculated forC₂₅H₃₁F₅N₅O₃ [M+H⁺]: 544, Found: 543.7.

(S)—N-(1-(Cyclobutylamino)-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl)-1-cyclopentyl-5-(3-(trifluoromethylpyridin-2-yl)-1H-pyrazole-3-carboxamide:A mixture of(S)-3-(1-cyclopentyl-5-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoicacid hydrochloride (40 mg, 0.073 mmol), cyclobutylamine (10 mg, 0.10mmol), Et₃N (0.030 ml, 0.29 mmol) and TBTU (24 mg, 0.10) in MeCN (5 ml)was stirred at rt for 15 h. The mixture was diluted with EtOAc andwashed with NaHCO₃. The organic layer was dried (Na₂SO₄), concentrated,and purified using 0-10% MeOH in DCM (with 1% NH₃) to give the titleproduct (34 mg) as a white solid; ¹H NMR (200 MHz, CDCl₃): δ=1.40-2.80(m, 28H), 4.30-4.50 (m, 3H), 6.42 (d, 1H, J=8.4 Hz), 6.90 (s, 1H),7.50-7.70 (m, 1H), 8.14 (d, 1H, J=8.2 Hz), 8.91 (d, 1H, J=4.0 Hz); LC-MS(ESI): m/z calculated for C₂₉H₃₈F₅N₆O₂ [M+H⁺]: 597, Found: 596.8; LCpurity: 96.4%.

3-Cyclohexylpropanal To a solution of commercially available3-cyclohexylpropanol (45.5 g, 0.32 mol) in CH₂Cl₂ (1000 mL) was addedPCC (103.5 g, 0.48 mol), Celite® 545 (50 g) and stirred at roomtemperature for 3 h. The reaction mixture was diluted with ethyl ether(1000 mL), stirred at rt for 1 h, before it was filtered through Celite®and silica gel (1:1) pad. The filtrate was concentrated to give cruderesidue. Crude product was purified by silica gel flash chromatography(0-30% EtOAc/hexanes) to give the title compound as oil (50.7 g), whichcontained residual hexanes as judged by NMR analysis. ¹H NMR (300 MHz,CDCl₃) δ0.83-0.98 (m, 3H), 1.15-1.31 (m, 4H), 1.49-1.56 (m, 2H),1.61-1.73 (m, 4H), 2.41-2.46 (m, 2H), 9.77 (s, 1H).

(E)-Tert-butyl 5-cyclohexylpent-2-enoate To a stirred solution oftert-butyl diethylphosphonoacetate (82.67 mL, 0.352 mol) in THF (500 mL)was slowly added n-BuLi (2.5 M in hexanes) (141 mL, 0.352 mol) dropwisewith cooling at −78° C. After stirring for 30 minutes at −78° C., asolution of 3-cyclohexylpropanal (50.7 g, 0.32 mol) in 250 mL of THFalso cooled at −78° C. was transferred via cannula. The resultingsolution was stirred at −78° C. for 40 minutes before being allowed towarm at rt and then stirred at 40 minutes. The solution was subsequentlycooled to −78° C. and quenched with sat. aqs. NH₄C₁ (250 mL). The layerswere separated and the aqueous layer was extracted in DCM (3×200 mL) andthe combined organics were dried over Na₂SO₄, filtered and the solventwas evaporated in vacuo to give the crude residue. Crude product waspurified by silica gel flash chromatography (0-2% EtOAc/hexanes) to givethe title compound as oil (59.8 g, 78%). ¹H NMR (300 MHz, CDCl₃) δ0.82-0.94 (m, 3H), 1.11-1.37 (m, 3H), 1.48 (s, 9H), 1.63-1.87 (m, 3H),2.14-2.21(m, 2H), 3.73-3.77 (m, 1H), 4.12-4.22 (m, 2H), 5.73 (dt,J=15.45, 1.51 Hz, 1H), 6.86 (m, 1H).

(S)-Tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-cyclohexylpentanoate: To a stirredsolution of (S)—N-benzyl-N-α-methylbenzylamine (84.86 g, 0.402 mol) inTHF (312 mL) was slowly added n-BuLi (2.5 M in hexanes) (161 mL, 0.402mol) with cooling at −78° C. After 30 minutes, a solution of(E)-tert-butyl 5-cyclohexylpent-2-enoate (59.81 g, 0.251 mol) in 100 mLof THF also at −78° C. was transferred via cannula. The resultingsolution was stirred at −78° C. for 3 h before quenching with sat. aqs.NH₄Cl (200 mL). Upon warming to rt, THF was removed and the aqueouslayer was extracted in DCM (3×200 mL). The combined organic layers werewashed with 10% aqs. citric acid (3×50 mL) to remove the excess amine.The organic layer was then washed with aqs. NaHCO₃ (50 mL), brine (50mL), dried with Na₂SO₄ and the solvent was removed in vacuo to give thecrude product. Crude product was purified by silica gel flashchromatography (0-2% EtOAc/hexanes) to give the title compound as oil(97.3 g, 86%). ¹H NMR (300 MHz, CDCl₃) δ 0.80-0.90 (m, 4H), 1.04-1.33(m, 9H), 1.39 (m, 9H), 1.60-1.74 (m, 4H), 1.82-1.99 (m, 2H), 3.21-3.29(m, 1H), 3.47 (d, J=14.69 Hz, 1H), 3.76-3.84 (m, 2H), 7.20-7.43 (m, 10H)

(S)-Tert-butyl 3-amino-5-cyclohexylpentanoate

A mixture of (S)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-5-cyclohexylpentanoate (50 g, 0.111mol) and 10% Pd/C (7.44 g) in 20% AcOH/EtOH (500 mL) was hydrogenated at45 psi for 24 h. The mixture was filtered through Celite® pad andconcentrated. The residue was dissolved in DCM (500 mL), basified withsat. sodium bicarbonate. The layers were separated and the aqueous layerwas extracted with DCM (3×200 mL). The combined DCM extracts were driedwith Na₂SO₄, filtered and solvent was removed in vacuo to obtain crudeproduct (28.3 g, 100%) as clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.85-0.95(m, 3H), 1.11-1.27 (m, 6H), 1.46 (s, 9H), 1.62-1.75 (m, 6H), 2.128-2.22(m, 1H), 2.34-2.40 (m, 1H), 3.05-3.14 (m, 1H)

(S)-Tert-butyl5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoate

1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid (100mg, 0.316 mmol) was dissolved in THF (5 mL). To the solution was addedbenzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (184 mg, 0.416 mmol) and triethylamine (0.130 mL, 0.948 mmol). Theresulting mixture was stirred at room temperature for 15 minutes.tert-butyl (S)-3-amino-5-cyclohexylpentanoate (89 mg, 0.347 mmol) in 0.4mL of THF was added dropwise, and stirred at room temperature for 3 h.THF was evaporated in vacuo, water was added to the residue and theaqueous layer was extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were washed with water, brine and then dried with Na₂SO₄,followed by filtration. The solvent was evaporated in vacuo. The residuewas purified by silica gel flash chromatography (EtOAc:Hex) to give thetitle compound as oil (152 mg, 87%). ¹H NMR (CDCl₃, 300 MHz) δ 0.81-0.96(m, 2H), 1.10-1.38 (m, 8H), 1.48 (s, 9H), 1.59-1.77 (m, 8H), 1.81-1.96(m, 4H), 2.00-2.16 (m, 2H), 2.55 (d, J=5.46 Hz, 2H), 3.73 (s, 3H), 3.74(s, 3H), 4.21-4.30 (m, 1H), 4.30-4.43 (m, 1H), 6.62 (d, J=8.48 Hz, 2H),6.67 (s, 1H), 7.25 (br. s., 1H), 7.37 (t, J=8.38 Hz, 1H). MS m/z: Calcd.for C₃₂H₄₇N₃O₅ 553.73 [M]⁺, found 555.0 [M+H]⁺,

(S)-5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoicacid

To a solution of (S)-tert-butyl5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoate(150 mg) in DCM (2 ml) was added HCl (4 M in dioxane, 0.7 ml). Themixture was stirred at rt for 15 h and concentrated to dryness to givethe acid as the HCl salt (120 mg). ¹H NMR (CDCl₃, 300 MHz) δ ppm0.78-1.00 (m, 3H), 1.09-1.40 (m, 6H), 1.49-1.77 (m, 4H), 1.71 (t, J=7.44Hz, 4H), 1.82-1.98 (m, 4H), 1.99-2.13 (m, 2H), 2.65-2.80 (m, 2H), 3.73(s, 3H), 3.74 (s, 3H), 4.21-4.33 (m, 2H), 6.63 (d, J=8.48 Hz, 2H), 6.68(s, 1H), 7.29 (s, 1H), 7.38 (t, J=8.38 Hz, 1H). MS (ESI) m/z: Calcd. forC₂₈H₃₉N₃O₅ 497.63 [M]⁺, found 496.7[M−H]⁻

(S)—N-(1-(cyclobutylamino)-5-cyclohexyl-1-oxopentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide

(S)-5-cyclohexyl-3-(1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)pentanoicacid (97 mg, 0.195 mmol) was dissolved in THF (5 mL). To the solutionwas added benzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP) (95 mg, 0.214 mmol) and triethylamine (0.080mL, 0.585 mmol). The resulting mixture was stirred at room temperaturefor 15 minutes. Cyclobutylamine (33 mg, 0.389 mmol) in 0.4 mL of THF wasadded dropwise, and stirred at room temperature for 3 h. THF wasevaporated in vacuo, water was added to the residue and the aqueouslayer was extracted with CH₂Cl₂ (3×15 mL). The combined organic layerswere washed with water, brine and then dried with Na₂SO₄, followed byfiltration. The solvent was evaporated in vacuo. The residue waspurified by silica gel flash chromatography (EtOAc:Hex) to give thetitle compound as white solid (80 mg, 75%). ¹H NMR (CDCl_(3, 300) MHz) δppm 0.88 (d, J=11.30 Hz, 2H), 1.12-1.39 (m, 6H), 1.60-1.77 (m, 9H),1.80-1.97 (m, 6H), 2.00-2.13 (m, 2H), 2.18-2.32 (m, 2H), 2.24 (d, J=7.16Hz, 2H), 2.53 (d, J=6.40 Hz, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 4.15-4.46(m, 3H), 6.63 (d, J=8.29 Hz, 2H), 6.67 (s, 1H), 6.75 (d, J=8.29 Hz, 1H),7.06 (d, J=9.04 Hz, 1H), 7.38 (t, J=8.38 Hz, 1H). MS (ESI) m/z: Calcd.for C₃₂H₄₆N₄O₄ 550.73 [M]⁺, found 551.6 [M+H]

Characterization of the Apelin Agonist Activity of the Compounds

The compounds above were studied for their in vitro activity as apelinagonists using the methods described by Giddings et al. Giddings et al.,2010 Int J High Thro Screen. 1:39-47, the contents of which are herebyincorporated by reference in its entirety. Using the methods describedin Giddings et al. and Apelin-13 as a positive control.

TABLE 2 EC₅₀ (nM) ID# IUPAC Name Ave 253(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-382 nM yl]formamido}-5-(piperidin-1-yl)pentanamide 296(3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-83 3-yl]formamido}-5-phenylpentanamide 297(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3- >10000yl]formamido}-4-phenylbutanoic acid 298(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-589 yl]formamido}pentanoic acid 299(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3- 2906yl]formamido}-5-phenylpentanoic acid 300(3R)-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3- >10000yl]formamido}-3-phenylpropanoic acid 301(3S)-6-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-2593 3-yl]formamido}hexanoic acid 302(2S)-N-cyclobutyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol- >100003-yl]formamido}-3-phenylpropanamide 303 tert-butyl(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(morpholin-4-yl)pentanoate 304 tert-butyl(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(4-methylpiperazin-1-yl)pentanoate 305 tert-butyl(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(diethylamino)pentanoate 306 tert-butyl(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-[(pyridin-4-ylmethyl)amino]pentanoate 307(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-6010 (morpholin-4-yl)pentanoic acid 308(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000(4-methylpiperazin-1-yl)pentanoic acid 309(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000(diethylamino)pentanoic acid 310(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000[(pyridin-4-ylmethyl)amino]pentanoic acid 311(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3- >10000yl]formamido}-4-phenylbutanoic acid 312(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-343 yl]formamido}-5-(morpholin-4-yl)pentanamide 313(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(4-methylpiperazin-1-yl)pentanamide 314(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-1845 yl]formamido}-5-(diethylamino)pentanamide 3151-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(4S)-2-oxo-1-(pyridin-4- >10000ylmethyl)piperidin-4-yl]-1H-pyrazole-3-carboxamide 316 tert-butyl(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(pyrrolidin-1-yl)pentanoate 317(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-9350 (pyrrolidin-1-yl)pentanoic acid hydrochloride 318(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-996 yl]formamido}-5-(pyrrolidin-1-yl)pentanamide 319 tert-butyl(3S)-5-(azepan-1-yl)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H- 3510pyrazol-3-yl]formamido}pentanoate 320 tert-butyl(3S)-5-{7-azabicyclo[2.2.1]heptan-7-yl}-3-{[1-cyclopentyl-5-(2,6- >10000dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanoate 321(3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-114 3-yl]formamido}-4-phenylbutanamide 322(3S)-5-(azepan-1-yl)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-1441 yl]formamido}pentanoic acid 323(3S)-5-{7-azabicyclo[2.2.1]heptan-7-yl}-3-{[1-cyclopentyl-5-(2,6- >10000dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanoic acid 324(3S)-5-(azepan-1-yl)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-107 1H-pyrazol-3-yl]formamido}pentanamide 325(3S)-5-{7-azabicyclo[2.2.1]heptan-7-yl}-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-3578 dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanamide 326(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-1041 (1-methylcyclobutyl)-5-(piperidin-1-yl)pentanamide 327(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-675 (3-methyloxetan-3-yl)-5-(piperidin-1-yl)pentanamide 328(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-ia (1-methylcyclopropyl)-5-(piperidin-1-yl)pentanamide 329(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-170 yl]formamido}-5-(2,6-dimethylpiperidin-1-yl)pentanamide 330(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-5165 (2,6-dimethylpiperidin-1-yl)pentanoic acid 331(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-353 yl]formamido}-N-methyl-5-(piperidin-1-yl)pentanamide 332(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-391 (oxan-4-yl)-5-(piperidin-1-yl)pentanamide 333(3S)-N-tert-butyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-2533 yl]formamido}-5-(piperidin-1-yl)pentanamide 334(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-6574 (2-methoxyethyl)-N-methyl-5-(piperidin-1-yl)pentanamide 335(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-63 yl]formamido}-5-(4,4-difluoropiperidin-1-yl)pentanamide 336(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-4738 (2-methoxyethyl)-5-(piperidin-1-yl)pentanamide 3371-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(3S)-1-{2-oxa-6-azaspiro[3.3]heptan- >100006-yl}-1-oxo-5-(piperidin-1-yl)pentan-3-yl]-1H-pyrazole-3-carboxamide 338(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-12 (piperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 339(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-31 (1,3-oxazol-2-yl)-5-(piperidin-1-yl)pentanamide 340(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-543 (1,3-oxazol-2-ylmethyl)-5-(piperidin-1-yl)pentanamide 341cyclobutyl(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-997 yl]formamido}-5-(piperidin-1-yl)pentanoate 342(3S)-3-(1-{5-[2,6-bis(2,2,2-trifluoroethoxy)phenyl]-1-cyclopentyl-1H-pyrazol-3- >10000yl}-N-ethylformamido)-N-cyclobutyl-5-(piperidin-1-yl)pentanamide 3431-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-1-(5-methyl-1,3,4-oxadiazol-2-1534 yl)-4-(piperidin-1-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 344(3S)-N-cyclobutyl-3-(1-{1-cyclopentyl-5-[2-(trifluoromethoxy)phenyl]-1H-2374 pyrazol-3-yl}-N-ethylformamido)-5-(piperidin-1-yl)pentanamide 345(3S)-N-cyclobutyl-3-{1-[1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazol- >100003-yl]-N-ethylformamido}-5-(piperidin-1-yl)pentanamide 346(3S)-N-cyclobutyl-3-{1-[5-(2,6-dimethoxyphenyl)-1-(pentan-3-yl)-1H-pyrazol-3- >10000yl]-N-ethylformamido}-5-(piperidin-1-yl)pentanamide 347(3S)-N-cyclobutyl-3-{1-[1-cyclopentyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl]-N- >10000ethylformamido}-5-(piperidin-1-yl)pentanamide 348(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-15 yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanamide 349(3S)-5-{2-azaspiro[3.3]heptan-2-yl}-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-197 dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pentanamide 350(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-720 (piperidin-1-yl)-N-(1H-1,2,3,4-tetrazol-5-yl)pentanamide 351(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-73 methyl-5-(piperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 352(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000(piperidin-1-yl)pentanamide 353(3S)-3-({5-[2,6-bis(2,2,2-trifluoroethoxy)phenyl]-1-cyclopentyl-1H-pyrazol-3- >10000yl}formamido)-N-cyclobutyl-5-(piperidin-1-yl)pentanamide 354(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,4,6-trifluorophenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(piperidin-1-yl)pentanamide 355(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(4-ethoxy-2,6-difluorophenyl)-1H-pyrazol-5085 3-yl]formamido}-5-(piperidin-1-yl)pentanamide 356(3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylcyclohexyl)-1H- >10000pyrazol-3-yl]formamido}-5-(piperidin-1-yl)pentanamide 357(3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(pentan-3-yl)-1H-pyrazol-3- >10000yl]formamido}-5-(piperidin-1-yl)pentanamide 3581-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(3S)-1-hydroxy-5-(piperidin-1- >10000yl)pentan-3-yl]-1H-pyrazole-3-carboxamide 359(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethoxy)phenyl]-1H-pyrazol-271 3-yl}formamido)-5-(piperidin-1-yl)pentanamide 360(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(methylsulfanyl)phenyl]-1H-pyrazol-3-376 yl}formamido)-5-(piperidin-1-yl)pentanamide 361(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-methoxyphenyl)-1H-pyrazol-3-234 yl]formamido}-5-(piperidin-1-yl)pentanamide 362(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(thiophen-2-yl)-1H-pyrazol-3- 5856yl]formamido}-5-(piperidin-1-yl)pentanamide 363(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3- 44yl]formamido}-5-(piperidin-1-yl)pentanamide 3641-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-(piperidin-1-yl)-1-(1H-1,2,3,4-235 tetrazol-5-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 365(3S)-N-cyclobutyl-3-[(1-cyclopentyl-5-phenyl-1H-pyrazol-3-yl)formamido]-5- >10000(piperidin-1-yl)pentanamide 366(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]- >100001H-pyrazol-3-yl}formamido)-5-(piperidin-1-yl)pentanamide 367(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-methanesulfonylphenyl)-1H-pyrazol-3-2966 yl]formamido}-5-(piperidin-1-yl)pentanamide 368(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(pyrimidin-5-yl)-1H-pyrazol-3- >10000yl]formamido}-5-(piperidin-1-yl)pentanamide 369(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(dimethyl-1,2-oxazol-4-yl)-1H-pyrazol-3- >10000yl]formamido}-5-(piperidin-1-yl)pentanamide 370(3S)-3-{[5-(2-chloro-6-methoxyphenyl)-1-cyclopentyl-1H-pyrazol-3- 1028yl]formamido}-N-cyclobutyl-5-(piperidin-1-yl)pentanamide 371(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethylphenyl)-1H-pyrazol-3-3841 yl]formamido}-5-(piperidin-1-yl)pentanamide 372(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazol-3-90 yl]formamido}-5-(piperidin-1-yl)pentanamide 373(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000(piperidin-1-yl)-N-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]pentanamide 3742-(3-{[(2S)-1-(cyclobutylcarbamoyl)-4-(piperidin-1-yl)butan-2-yl]carbamoyl}-1- >10000cyclopentyl-1H-pyrazol-5-yl)pyridin-1-ium-1-olate 375(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(pyridin-2-yl)-1H-pyrazol-3- >10000yl]formamido}-5-(piperidin-1-yl)pentanamide 376(2S)-N-cyclobutyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-3-cyclopropylpropanamide 377(2S)-N,3-dicyclobutyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}propanamide 378(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(1,3-thiazol-4-yl)-1H-pyrazol-3-9386 yl]formamido}-5-(piperidin-1-yl)pentanamide 379(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-1407 (piperidin-1-yl)-N-(1H-1,2,3,4-tetrazol-5-ylmethyl)pentanamide 380(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-94 phenyl-N-(1,3-thiazol-2-yl)pentanamide 381(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-647 phenyl-N-(1H-1,2,3,4-tetrazol-5-yl)pentanamide 382(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-3441 phenyl-N-(1,3-thiazol-2-ylmethyl)pentanamide 383(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-5177 phenyl-N-(1H-1,2,3,4-tetrazol-5-ylmethyl)pentanamide 384(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-15 (3,3-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 385(2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-3- >10000cyclopropylpropanoic acid 386(2S)-3-cyclobutyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-6170 yl]formamido}propanoic acid 387(2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4-8716 phenyl-N-(1H-1,2,3,4-tetrazol-5-ylmethyl)butanamide 388(2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4-399 phenyl-N-(1,3-thiazol-2-ylmethyl)butanamide 389(2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000phenylbutanoic acid 3901-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-phenyl-1-(1H-1,2,3,4-tetrazol-429 5-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 391N-[(2S)-1-cyano-4-phenylbutan-2-yl]-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-6344 pyrazole-3-carboxamide 392(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5- >10000phenylpentanamide 393(2S)-3-cyclopentyl-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-424 yl]formamido}propanoic acid 395(2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000phenyl-N-(1H-1,2,3,4-tetrazol-5-yl)butanamide 396(2S)-2-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000phenyl-N-(1,3-thiazol-2-yl)butanamide 397(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(propan-2-yl)phenyl]-1H-pyrazol-3-140 yl}formamido)-5-(piperidin-1-yl)pentanamide 398N-[(3R)-1-(cyclobutylamino)-5-(piperidin-1-yl)pentan-3-yl]-1-cyclopentyl-5-(2,6- >10000dimethoxyphenyl)-1H-pyrazole-3-carboxamide 399(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethyl-4-fluorophenyl)-1H-pyrazol-3-264 yl]formamido}-5-(piperidin-1-yl)pentanamide 400(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-46 3-yl}formamido)-5-(piperidin-1-yl)pentanamide 401(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4- >10000phenylbutanoic acid 402(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4-203 phenyl-N-(1,3-thiazol-2-yl)butanamide 403(3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-42 (piperidin-1-yl)pentanoic acid hydrochloride 404(3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(3,3-65 difluoropiperidin-1-yl)pentanoic acid 405(3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(4,4-227 difluoropiperidin-1-yl)pentanoic acid 406(3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-22 (piperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 407(3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N-162 cyclobutyl-5-(piperidin-1-yl)pentanamide 408(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-64 yl}formamido)-5-(piperidin-1-yl)pentanamide 409(3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(4,4-12.5 difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 410(3S)-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3-yl]formamido}-5-(3,3-7 difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 411(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3- 14.5yl]formamido}-5-(4,4-difluoropiperidin-1-yl)pentanamide 412(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethylphenyl)-1H-pyrazol-3- 5yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanamide 413(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-cyclopropylphenyl)-1H-pyrazol-3-49 yl]formamido}-5-(piperidin-1-yl)pentanamide 4141-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-(piperidin-1-yl)-1-(4H-1,2,4-200 triazol-3-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 415(3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-292 yl]formamido}-5-(4-fluorophenyl)pent-4-enamide 416(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-606 yl]formamido}-5-(4-fluorophenyl)pentanamide 417(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-36 (4-fluorophenyl)-N-(1,3-thiazol-2-yl)pentanamide 418(3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-664 yl]formamido}-5-(pyridin-3-yl)pent-4-enamide 419(3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}-5-(pyridin-4-yl)pent-4-enamide 420(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-883 yl]formamido}-5-(pyridin-3-yl)pentanamide 421(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-3312 yl]formamido}-5-(1-methylpiperidin-4-yl)pentanamide 4221-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-1-(1,3,4-oxadiazol-2-yl)-4-1422 (piperidin-1-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 423(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 35yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 424(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 110yl}formamido)-5-(4,4-difluoropiperidin-1-yl)pentanoic acid 425(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-10.9 yl}formamido)-5-(3,3-difluoropiperidm-1-yl)pentanamide 426(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 10.6yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide427 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-8.5yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(1,3-oxazol-2-yl)pentanamide428 (3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3-7.5yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide429(3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3-6.1 difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 430(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 17.5yl}formamido)-5-(4,4-difluoropiperidin-1-yl)-N-(1,3-thiazol-2-yl)pentanamide431 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-22.5yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-methyl-N-(1,3-thiazol-2-yl)pentanamide 432(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 16yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 433(3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3-151 difluoropiperidin-1-yl)pentanoic acid 434(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)thiophen-3-yl]-1H-641 pyrazol-3-yl}formamido)-5-(piperidin-1-yl)pentanamide 435(3R,4E)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-9211 yl]formamido}-5-(pyridin-2-yl)pent-4-enamide 436(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 58yl}formamido)-5-(4,4-difluoropiperidin-1-yl)-N-(5-methyl-1,3-thiazol-2-yl)pentanamide 4371-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(4H-1,2,4-triazol-3-21yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide438(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2-ethynylphenyl)-1H-pyrazol-3-290 yl]formamido}-5-(piperidin-1-yl)pentanamide 439(3S)-N-benzyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-920 yl}formamido)-5-(4,4-difluoropiperidin-1-yl)pentanamide 440(3S)-N-(cyclohexylmethyl)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-301 pyrazol-3-yl}formamido)-5-(4,4-difluoropiperidin-1-yl)pentanamide441(3S)-N-benzyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000yl}formamido)-5-methylhexanamide 442N-benzyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000yl}formamido)propanamide 443(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-N-73 (3,3-difluorocyclobutyl)-5-(piperidin-1-yl)pentanamide 4451-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-1-(1-methyl-1H-1,2,3,4-tetrazol-2835 5-yl)-4-(piperidin-1-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 447(3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3-84 difluoropiperidin-1-yl)-N-methyl-N-(1,3-thiazol-2-yl)pentanamide 4481-cyclopentyl-5-(2,6-dimethoxyphenyl)-N-[(2S)-4-(piperidin-1-yl)-1-(1,3-thiazol-1338 2-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 4493-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)-N-12670 (1,3-thiazol-2-yl)propanamide 4505-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(4H-30 1,2,4-triazol-3-yl)butan-2-yl]-1H-pyrazole-3-carboxamide 451(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 27yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-methyl-N-(1,3-oxazol-2-yl)pentanamide 452(3S)-3-{[5-(2-chlorophenyl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-(3,3-70 difluoropiperidin-1-yl)-N-methyl-N-(1,3-oxazol-2-yl)pentanamide 457(3S)-3-{[5-(3-chloropyridin-4-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N-1324 cyclobutyl-5-(3,3-difluoropiperidin-1-yl)pentanamide 4585-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(5-261 methyl-4H-1,2,4-triazol-3-yl)butan-2-yl]-1H-pyrazole-3-carboxamide4595-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-[5-243(trifluoromethyl)-4H-1,2,4-triazol-3-yl]butan-2-yl]-1H-pyrazole-3-carboxamide460(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1H-23 pyrazol-3-yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanamide 463(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1236yl}formamido)-5-(4-fluorophenyl)pentanoic acid 4641-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-(hydrazinecarbonyl)butan-2-yl]-5-[2-1036 (trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 4655-(2-chlorophenyl)-1-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-191 (hydrazinecarbonyl)butan-2-yl]-1H-pyrazole-3-carboxamide 466(3S)-3-{[5-(4-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N-1217 cyclobutyl-5-(3,3-difluoropiperidin-1-yl)pentanamide 467(3S)-3-{[5-(4-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5- >10,000(3,3-difluoropiperidin-1-yl)pentanoic acid 468(3S)-3-{[5-(2-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-5-1674 (3,3-difluoropiperidin-1-yl)pentanoic acid 469(3S)-3-{[5-(2-chloropyridin-3-yl)-1-cyclopentyl-1H-pyrazol-3-yl]formamido}-N-133 cyclobutyl-5-(3,3-difluoropiperidin-1-yl)pentanamide 4701-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-(4H-1,2,4-triazol-3-yl)butan-2-yl]-5-435 [2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 4711-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-(5-methyl-4H-1,2,4-triazol-3-1144yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide4751-cyclopentyl-N-[(2S)-4-(4-fluorophenyl)-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-1462-yl]butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide479(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1H-0.86 pyrazol-3-yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanamide480(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-2.76 yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)pentanamide 481(3S)-5-(3-cyanopyrrolidin-1-yl)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-1.96 (trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 482(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 474yl}formamido)-5-(4-fluorophenyl)-N-(1-methylazetidin-3-yl)pentanamide483(3S)-N-cyclobutyl-5-[cyclohexyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 14(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 484(3S)-5-cyclohexyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-1518 yl}formamido)pentanoic acid 485(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 110yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)pentanoic acid 486(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 931yl}formamido)-5-(morpholin-4-yl)pentanoic acid 487(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol- 2773-yl}formamido)-5-[(2S)-2-(trifluoromethyl)piperidin-1-yl]pentanoic acid488 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-1342 yl}formamido)-5-[(2R)-2-(trifluoromethyl)piperidin-1-yl]pentanoicacid 489(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 161yl}formamido)-N-methyl-N-(1,3-thiazol-2-yl)-5-[(2R)-2-(trifluoromethyl)piperidin-1-yl]pentanamide 490(3S)-N-cyclobutyl-5-[cyclopentyl(methyl)amino]-3-({1-cyclopentyl-5-[2-10.3 (trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 491(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-68 yl}formamido)-5-(morpholin-4-yl)pentanamide 492(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-36 yl}formamido)-5-(dipropylamino)pentanamide 493(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-24 yl}formamido)-5-[methyl(2-methylpropyl)amino]pentanamide 494(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 215yl}formamido)-5-(piperidin-1-yl)pentanoic acid 495(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 165yl}formamido)-N-methyl-5-(morpholin-4-yl)-N-(1,3-thiazol-2-yl)pentanamide496(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-30 yl}formamido)-5-[(2S)-2-(trifluoromethyl)piperidin-1-yl]pentanamide497(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-103 yl}formamido)-5-(4-fluorophenyl)pentanamide 498(3S)-5-{8-azabicyclo[3.2.1]octan-8-yl}-N-cyclobutyl-3-({1-cyclopentyl-5-[2-105 (trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 499(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 548yl}formamido)-5-(pyrrolidin-1-yl)pentanoic acid 500(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 79yl}formamido)-N-methyl-5-(4-methyl-1H-pyrazol-1-yl)-N-(1,3-thiazol-2-yl)pentanamide 501(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-26 yl}formamido)-5-(4-methyl-1H-pyrazol-1-yl)pentanamide 502(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 77yl}formamido)-5-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methyl-N-(1,3-thiazol-2-yl)pentanamide 503(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-157 yl}formamido)-5-(3,5-dimethyl-1H-pyrazol-1-yl)pentanamide 504(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-59 yl}formamido)-5-(pyrrolidin-1-yl)pentanamide 505(3S)-5-(azepan-1-yl)-N-cyclobutyl-3-({1-cyclopentyl-5-[2- 34(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 506(3S)-N-cyclobutyl-5-[cyclobutyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 32(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 507(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-162 yl}formamido)-5-{2-oxa-6-azaspiro[3.3]heptan-6-yl}pentanamide 508(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 475yl}formamido)-5-oxo-5-(piperidin-1-yl)pentanoic acid 509(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1065yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-5-oxopentanoic acid 510(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 2192yl}formamido)-5-(4-fluorophenyl)-N-(pyrrolidin-1-yl)pentanamide 511(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-35 yl}formamido)-5-[methyl(1-methylcyclopentyl)amino]pentanamide 514(3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-79 yl}formamido)-5-oxo-5-(piperidin-1-yl)pentanamide 515(3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-47 yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-5-oxopentanamide 516(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-834 yl}formamido)-5-(dimethylamino)pentanamide 517(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-261 yl}formamido)-5-(2,2-dimethylpiperidin-1-yl)pentanamide 518(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000yl}formamido)-4-(3,3-difluoropyrrolidin-1-yl)butanoic acid 519(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000yl}formamido)-4-(3,3-difluoropiperidin-1-yl)butanoic acid 520(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 45yl}formamido)-N-(3,3-difluorocyclobutyl)-5-(piperidin-1-yl)pentanamide521(3S)-5-{2-azabicyclo[2.2.2]octan-2-yl}-N-cyclobutyl-3-({1-cyclopentyl-5-[2-100 (trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)pentanamide 522(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-64 yl}formamido)-5-{2-oxa-5-azaspiro[3.5]nonan-5-yl}pentanamide 523(3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-1207 yl}formamido)-4-(3,3-difluoropyrrolidin-1-yl)butanamide 524(3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-910 yl}formamido)-4-(3,3-difluoropiperidin-1-yl)butanamide 525(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-1,2,4-triazol-3- >10,000yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 526(2S)-3-cyclopentyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-1717 yl}formamido)propanoic acid 527(2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000yl}formamido)-4-methylpentanoic acid 528(2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- >10,000yl}formamido)-3-methylbutanoic acid 529(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 134yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-N-(trifluoromethane)sulfonylpentanamide 533(3R)-4-[cyclohexyl(methyl)amino]-3-({1-cyclopentyl-5-[2- 822(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)butanoic acid 534(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 388yl}formamido)-5-(3,3-difluoroazetidin-1-yl)pentanoic acid 535(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-32 yl}formamido)-5-(3,3-difluoroazetidin-1-yl)pentanamide 536(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-39 yl}formamido)-5-(cyclopentylformamido)pentanamide 537(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 16yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)pentanoic acid 538(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 544yl}formamido)-5-(cyclopentylformamido)pentanoic acid 539(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-176 yl}formamido)-5-(oxetan-3-ylformamido)pentanamide 5401-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-4-oxo-1-sulfamoylbutan-2-1382 yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 541N-[(2S)-1-(cyclobutylsulfamoyl)-4-(3,3-difluoropiperidin-1-yl)-4-oxobutan-2-yl]-10581-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide542 (2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-105 yl}formamido)-N-(2-methoxyethyl)-N-methyl-4-phenylbutanamide 544(3R)-3-(cyclohexylcarbamoyl)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-205 1H-pyrazol-3-yl}formamido)propanoic acid 545(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1233yl}formamido)-4-(4-fluorophenoxy)butanoic acid 546(3R)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-114 yl}formamido)-4-(4-fluorophenoxy)butanamide 547(3R)-N-cyclobutyl-4-[cyclohexyl(methyl)amino]-3-({1-cyclopentyl-5-[2-5125 (trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)butanamide 548(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 255yl}formamido)-5-[(3,3-difluorocyclobutyl)amino]pentanoic acid 549(2R)-N-cyclobutyl-N′-cyclohexyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-152 1H-pyrazol-3-yl}formamido)butanediamide 550(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 8679yl}formamido)-N-(3-methyloxetan-3-yl)-5-oxo-5-(piperidin-1-yl)pentanamide5511-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(1H-1,2,3,4-tetrazol-5-25yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide552(3S)-3-({1-cyclobutyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)-167 5-(3,3-difluoropiperidin-1-yl)pentanoic acid 553(3S)-5-(3,3-difluoropiperidin-1-yl)-3-{[1-(oxan-4-yl)-5-[2- 1482(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]formamido}pentanoic acid 554(3S)-3-({1-cyclopentyl-5-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrazol-3-126 yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 555(3S)-3-({5-[4-chloro-2-(trifluoromethyl)phenyl]-1-cyclopentyl-1H-pyrazol-3-1573 yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 556(3S)-3-({5-[2-chloro-6-(trifluoromethyl)phenyl]-1-cyclopentyl-1H-pyrazol-3- >10yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 557(3S)-3-{[1-(cyclopropylmethyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-401 yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 558(3R)-3-[cyclohexyl(methyl)carbamoyl]-3-({1-cyclopentyl-5-[2- 1172(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}formamido)propanoic acid 559(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 596yl}formamido)-3-[(oxan-4-yl)carbamoyl]propanoic acid 560(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 738yl}formamido)-3-[(4-fluorophenyl)carbamoyl]propanoic acid 561(2R)-N-cyclobutyl-N′-cyclohexyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-879 1H-pyrazol-3-yl}formamido)-N′-methylbutanediamide 562(2R)-N-cyclobutyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-169 yl}formamido)-N′-(oxan-4-yl)butanediamide 5631-cyclopentyl-N-[(3R)-1-(4-fluorophenyl)-2,5-dioxopyrrolidin-3-yl]-5-[2- >10,000(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 564(2S)-2-({1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-982 yl}formamido)-N-(2-methoxyethyl)-N-methyl-4-phenylbutanamide 565(3S)-5-(3,3-difluoropiperidin-1-yl)-3-{[1-(2-methylpropyl)-5-[2- 544(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]formamido}pentanoic acid 566(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 3051yl}formamido)-5-(3,3,4,4,5,5-hexafluoropiperidin-1-yl)pentanoic acid 567(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 648yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanoic acid 568(3S)-5-(3,3-difluoropiperidin-1-yl)-3-{[1-(2,2-dimethylpropyl)-5- >10,000[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]formamido}pentanoic acid 570(2S)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 4250yl}formamido)-N-(2-methoxyethyl)-N-methyl-3-phenoxypropanamide 571(3S)-3-{[1-(cyclobutylmethyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-130 yl]formamido}-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 572(3S,5S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-124 yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanoic acid 573(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-299 yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanamide 574(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 981yl}formamido)-5-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pentanoic acid 575(3S,5R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 91yl}formamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid 576(3S,5S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-1374 yl}formamido)-5-(3,3-difluoropiperidin-1-yl)hexanoic acid 577(2S)-3-cyclohexyl-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-1026 yl}formamido)propanoic acid 578(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 78yl}formamido)-5-[3-(trifluoromethyl)pyrrolidin-1-yl]pentanoic acid 579(3R)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1874yl}formamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid 580(3S)-5-(3,3-difluoropiperidin-1-yl)-3-({1-propyl-5-[2-(trifluoromethyl)phenyl]-1H-718 pyrazol-3-yl}formamido)pentanoic acid 581(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 215yl}formamido)-5-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]pentanoic acid 582(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 109yl}formamido)-5-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pentanoic acid 583(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 302yl}formamido)-5-[(3S)-3-fluoropiperidin-1-yl]pentanoic acid 584(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 184yl}formamido)-5-[(3R)-3-fluoropiperidin-1-yl]pentanoic acid 585(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 654yl}formamido)-5-[(3S)-3-fluoropyrrolidin-1-yl]pentanoic acid 587(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 355yl}formamido)-5-(2-oxopiperidin-1-yl)pentanoic acid 588(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 502yl}formamido)-5-(3,3-dimethylazetidin-1-yl)pentanoic acid 589(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 171yl}formamido)-5-(3,3-difluoroazetidin-1-yl)pentanoic acid 590(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1159yl}formamido)-5-[(3R)-3-fluoropyrrolidin-1-yl]pentanoic acid 591(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 528yl}formamido)-5-{5,5-difluoro-2-azaspiro[3.3]heptan-2-yl}pentanoic acid592(2S)-3-(tert-butoxy)-2-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5549 3-yl}formamido)-N-(2-methoxyethyl)-N-methylpropanamide 593(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 79yl}formamido)-5-[(3R)-3-fluoropiperidin-1-yl]pentanoic acid 594(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 44yl}formamido)-5-[trans-3,4-difluoropyrrolidin-1-yl]pentanoic acid 595(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 140yl}formamido)-5-[trans-3,4-dimethylpyrrolidin-1-yl]hexanoic acid 596(2S,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 88yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoic acid 597(2R,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 23yl}formamido)-5-(3,3-difluoropiperidin-1-yl)-2-methylpentanoic acid 598(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 103yl}formamido)-5-[cis-3,4-difluoropyrrolidin-1-yl]pentanoic acid 599(3S,5R)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3-24 yl}formamido)-5-[trans-3,4-difluoropyrrolidin-1-yl]hexanoic acid 600(3S,5S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3-67 yl}formamido)-5-(3,3-difluoropyrrolidin-1-yl)hexanoic acid 601(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 128yl}formamido)-5-[3-(trifluoromethyl)azetidin-1-yl]pentanoic acid 602(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 346yl}formamido)-5-{3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl}pentanoicacid 603(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 46yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pentanoicacid 604(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 55yl}formamido)-5-(2,6-dioxopiperidin-1-yl)pentanoic acid 605(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 11yl}formamido)-5-[(2R)-4,4-difluoro-2-methylpyrrolidin-1-yl]pentanoicacid 606(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 310yl}formamido)-5-{8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl}pentanoicacid 607(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 69yl}formamido)-5-(5,5-difluoro-2-methylpiperidin-1-yl)pentanoic acid 608(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 1074yl}formamido)-5-(2,2-dimethyl-4-oxopyrrolidin-1-yl)pentanoic acid 609(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 98yl}formamido)-5-(3-fluoro-3-methylpyrrolidin-1-yl)pentanoic acid 610(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 43yl}formamido)-5-[(3S,4R)-3,4-difluoropiperidin-1-yl]pentanoic acid 611(3S)-3-({1-cyclopentyl-5-[2-(1,1-difluoroethyl)phenyl]-1H-pyrazol-3- 509yl}formamido)-5-(2,2-dimethyl-4-oxopiperidin-1-yl)pentanoic acid 612(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 231yl}formamido)-5-(4,4-difluoro-2,2-dimethylpyrrolidin-1-yl)pentanoic acid613 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-104 yl}formamido)-5-(3-fluoro-3-methylpiperidin-1-yl)pentanoic acidtrifluoroacetate 614(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 41yl}formamido)-5-[(3S)-3-fluoro-3-methylpiperidin-1-yl]pentanoic acid 615(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 353yl}formamido)-5-{[1-(trifluoromethyl)cyclopentyl]amino}pentanoic acidtrifluoroacetate 618(3S)-N-cyclobutyl-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-425 1H-pyrazol-3-yl]formamido}pentanamide 621(3S)-5-cyclohexyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-424 yl]formamido}pentanoic acid 622(3S)-5-cyclohexyl-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-380 yl]formamido}pentanoic acid 623(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-propyl-1H-pyrazol-3- 416yl]formamido}pentanoic acid 624(3S)-N-cyclobutyl-5-cyclohexyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-70 pyrazol-3-yl]formamido}pentanamide 625(3S)-N-cyclobutyl-5-cyclohexyl-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-101 pyrazol-3-yl]formamido}pentanamide 626(3S)-N-cyclobutyl-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-propyl-1H-49 pyrazol-3-yl]formamido}pentanamide 6281-cyclopentyl-N-[(2S)-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-1-(1H-611,2,3,4-tetrazol-5-yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 629(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 77yl}formamido)-5-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pentanoic acid 6301-cyclopentyl-N-[(2S)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-1-(1H-1,2,3,4-24tetrazol-5-yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 631(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 75yl}formamido)-5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]pentanoic acid 634(2S,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 87yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpentanoicacid 635(2R,3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 13yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpentanoicacid 636(3S)-N-cyclobutyl-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-158 yl}formamido)-5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpentanamide 6371-cyclopentyl-N-[(3S)-1-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-(1H-211,2,3,4-tetrazol-5-yl)pentan-3-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 6381-cyclopentyl-N-[(3S,4R)-1-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-(1H-141,2,3,4-tetrazol-5-yl)pentan-3-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide 639(3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- 40yl}formamido)-5-(3,5-difluoropiperidin-1-yl)pentanoic acid 6411-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(1H-1,2,3,4-tetrazol-5-27yl)butan-2-yl]-5-[3-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3-carboxamide643 (3S)-3-({1-cyclopentyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3-182 yl}formamido)-5-(2,5-dioxopyrrolidin-1-yl)pentanoic acid 646(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-methyl-1H-pyrazol-3-1476 yl]formamido}pentanoic acid 647(3S)-5-cyclohexyl-3-{[1-cyclooctyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3- >10000yl]formamido}pentanoic acid 648(3S)-5-cyclohexyl-3-{[1-(cyclohexylmethyl)-5-(2,6-dimethoxyphenyl)-1H- >10000pyrazol-3-yl]formamido}pentanoic acid 649(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(pentan-3-yl)-1H-pyrazol-3- >10000yl]formamido}pentanoic acid 6551-cyclopentyl-N-[(2S)-4-(2,6-dioxopiperidin-1-yl)-1-(1H-1,2,3,4-tetrazol-5-66yl)butan-2-yl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide

5.3. Cellular Uptake Assay

Caco-2 cells (clone C2BBe1) were obtained from American Type CultureCollection (Manassas, Va.). Cell monolayers were grown to confluence oncollagen-coated, microporous, polycarbonate membranes in 12-well CostarTranswell plates. Details of the plates and their certification areshown below. The permeability assay buffer was Hanks' balanced saltsolution (HBSS) containing 10 mM HEPES and 15 mM glucose at a pH of 7.4.The buffer in the receiver chamber also contained 1% bovine serumalbumin. The dosing solution concentration was 5 μM for each testarticle in the assay buffer. Cell monolayers were dosed on the apicalside (A-to-B) or basolateral side (B-to-A) and incubated at 37° C. with5% CO₂ in a humidified incubator. Samples were taken from the donor andreceiver chambers at 120 minutes. Each determination was performed induplicate. After the experiment, all assay buffers were removed from theinserts. Cell monolayers were dosed with blank 500 μM lucifer yellow onthe A-to-B side and blank HBSS on the B-to-A side and incubated at 37°C. Samples were taken from the B-to-A side at 60 minutes. The flux oflucifer yellow was measured for each monolayer to ensure no damage wasinflicted to the cell monolayers during the flux period. All sampleswere analyzed by LC-MS/MS using electrospray ionization. The apparentpermeability (P_(app)) and percent recovery were calculated as follows:

P _(app)=(dC _(r) /dt)×V _(r)/(A×C _(A))   (1)

Percent Recovery=100×((V _(r) ×C _(r) ^(final))+(V _(d) ×C _(d)^(final)))/(V _(d) ×C _(N))   (2)

Where, dC_(r)/dt is the slope of the cumulative concentration in thereceiver compartment versus time in μM s⁻¹;

V_(r) is the volume of the receiver compartment in cm³;

V_(d) is the volume of the donor compartment in cm³;

A is the area of the insert (1.13 cm² for 12-well Transwell);

C_(A) is the average of the nominal dosing concentration and themeasured 120-minute donor concentration in μM;

C_(N) is the nominal concentration of the dosing solution in μM;

C_(r) ^(final) is the cumulative receiver concentration in μM at the endof the incubation period;

C_(d) ^(final) is the concentration of the donor in μM at the end of theincubation period.

Efflux ratio (ER) is defined as P_(app) (B-to-A)/P_(app) (A-to-B).

Absorption Potential Classification:

P_(app) (A-to-B)<1.0×10⁻⁶ cm/s: Low

P_(app) (A-to-B)≥1.0×10⁻⁶ cm/s: High

Significant Efflux is defined as: ER≥2.0 and P_(app) (B-to-A)≥1.0×10⁻⁶cm/

TABLE 3 Cellular Uptake Results ID # EC50 (nM) Efflux ratio 253 382 34348 15 2.1 335 63 1 363 44 3.6 384 15 1.7 410 7 1

In Vivo Blood Pressure Lowering Activity of the Compounds

Select compounds were evaluated for their effects upon oraladministration on hemodynamic changes, including blood pressurereduction, in conscious, telemetered male Sprague-Dawley rats. Apelinpeptides are known to lower blood pressure, e.g., Tatemoto, K., et.al.Regul. Pept. 2001, 99, 87-92.

Animals were approximately 7-9 weeks of age and weighed between 247 g to263 g just prior to surgery. Dose levels administered were 7.5, 15 or 30mg/kg, dose volumes were 10 mL/kg, and dose route of administration wasoral gavage. Animals were assigned to a crossover experimental treatmentschedule as shown below.

Animal Treatment 1 Treatment 2 Treatment 3 Treatment 4 No. Compound(mg/kg) 1 30 15 7.5 0 (vehicle) 2 15 7.5 0 (vehicle) 30 3 7.5 0(vehicle) 30 15 4 0 (vehicle) 30 15 7.5 5 30 15 7.5 0 (vehicle) 6 15 7.50 (vehicle) 30 7 7.5 0 (vehicle) 30 15 8 0 (vehicle) 30 15 7.5

Collected data included systolic, diastolic, and mean arterial bloodpressure (MAP). Data collection time points were for pre-dose baselineapproximately 48 h (prior to treatment 1) or approximately 24 h (priorto treatment 2-4) for 10 sec every 2 min. Data collection post-dose wascollected through approximately 24 h (data collected for 10 sec every 2min) per treatment. Resulting data is presented below as the 2-5 h meanchange from baseline in mmHg.

Compound 423 Compound 551 Systolic Diastolic MAP Systolic Diastolic MAPVehicle −3.7 −3.2 −4.7 −2.6 −2.1 −2.4 (0 mg/kg) 7.5 mg/kg  −13.0 −9.9−10.0 −6.6 −4.3 −4.5 15 mg/kg −9.8 −7.3 −8.4 −9.6 −7.3 −8.5 30 mg/kg−10.7 −8.3 −9.3 −11.3 −8.4 −9.8

Compound 423 treatment via oral gavage to male Sprague-Dawley ratsresulted in a mild sustained decrease in blood pressure, and compound551 treatment resulted in a dose-dependent, mild sustained decrease inblood pressure.

It is to be understood that, while the disclosure has been described inconjunction with the detailed description, thereof, the foregoingdescription is intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages, and modifications of thedisclosure are within the scope of the claims set forth below. Allpublications, patents, and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application was specifically and individuallyindicated to be incorporated by reference.

1.-20. (canceled)
 21. A compound represented by the Formula IV:

or a pharmaceutically acceptable salt, a prodrug, or a salt of aprodrug, wherein R₁ is represented by the formula:

wherein

is a monocyclic aryl or heteroaryl group; each A is independently C₁₋₈alkoxy, halogen, fluoro substituted C₁-C₃ alkoxy, or fluoro substitutedC₁-C₃ alkyl; n is 1 or 2; R₂ is optionally substituted C₃₋₈ alkyl, C₁₋₈alkyl (C₃₋₈ cycloalkyl), C₃₋₈ cycloalkyl, or heteroaryl; R₃ is absent;R₄ is optionally substituted C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈ cycloalkyl,C₁₋₈ alkyl(aryl), C₁₋₈ alkyl(C₃₋₈ cycloalkyl), C₁₋₈ alkyl(heteroaryl),or (CH₂)_(x)(NR₇R₈; R₅ is optionally substituted adamantanyl, aryl, C₁₋₈alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₂₋₈alkyl(aryl), C₁₋₈ alkyl(C₃₋₈ cycloalkyl), C₁₋₈ alkyl(C₃₋₈cycloalkyl)-CO₂R₇, C₁₋₈ alkyl(guanidinyl), C₁₋₈ alkyl(heteroaryl), C₁₋₈alkyl(tetrazol-5-one), C₂₋₄ alkyl(heterocycloalkyl), C₁₋₈alkyl(thioether), C₁₋₈ alkyl(thiol), C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl),C₂₋₈ alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-CO₂R₇, (CH₂)_(x)NR₇R₈, (CH₂)_(x)OR₇, (CH₂)_(x)NR₉COR₇,(CH₂)_(x)NR₉SO₂R₇, (CH₂)_(x)NR₉CO₂R₇, (CH₂)_(x)NHCOR₇, (CH₂)_(x)NHSO₂R₇,(CH₂)_(x)NHCO₂R₇, (CH₂)_(x)CONR₇R₈, (CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉,(CH₂)_(x)CONR₇(CH₂)_(y)CONR₇R₈, (CH₂)_(x)CONR₇(CH₂)_(y)R₉,(CH₂)_(x)COR₇, (CH₂)_(x)CO₂R₇, (CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉, CHR₇COR₉,CHR₇CONHCHR₈COR₉, CONR₇R₈, CONR₇(CH₂)_(x)CO₂R₈, CONR₇CHR₈CO₂R₉, CO₂R₉,NHCO₂R₇, or (CH₂)_(x) SO₂NR₇R₈; R₆ is H; or R₄ and R₅ together make a4-8 member ring which may be substituted with one or more heteroatoms;or R₄ and R₅ together make a 5-8 member nitrogen-containing ring withone or more carbonyl groups; R₇ and R₅ each are independently H, C₁₋₈alkoxy, aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈alkyl amido, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈ alkyltetrazol-5-one, C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈ alkylthioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈cycloalkyl, (CH₂)_(x)CONHR₉, (CH₂)_(x)COR₉, (CH₂)_(x)CO₂R₉, orheteroaryl; or R₇ and R₈ together make a 3-9 member ring which maycontain one or more heteroatoms; or R₇ and R₅ together make a 5-8 membernitrogen-containing ring with one or more carbonyl groups; R₉ is H, C₁₋₈alkoxy, C₁₋₈ alkyl, C₁₋₈ alkyl(aryl), C₃₋₈ cycloalkyl, aryl, heteroaryl,or hydroxyl; each x is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; andeach y is independently 1, 2, 3, 4, 5, 6, 7, or 8; and Z is O.
 22. Thecompound of claim 21, wherein R₅ is optionally substituted adamantanyl,aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino, C₁₋₈ alkylamido, C₂₋₈ alkyl(aryl), C₁₋₈ alkyl(C₃₋₈ cycloalkyl), C₁₋₈ alkyl(C₃₋₈cycloalkyl)-CO₂R₇, C₁₋₈ alkyl(guanidinyl), C₁₋₈ alkyl(heteroaryl), C₁₋₈alkyl(tetrazol-5-one), C₂₋₄ alkyl(heterocycloalkyl), C₁₋₈alkyl(thioether), C₁₋₈ alkyl(thiol), C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl),C₂₋₈ alkenyl(heteroaryl), C₃₋₈ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-CO₂R₇, (CH₂)_(x)NR₇R₈, (CH₂)_(x)OR₇, (CH₂)_(x)NR₉COR₇,(CH₂)_(x)NR₉SO₂R₇, (CH₂)_(x)NR₉ CO₂R₇, (CH₂)_(x)NHCOR₇,(CH₂)_(x)NHSO₂R₇, (CH₂)_(x)(NHCO₂R₇, (CH₂)_(x)CONR₇R₈,(CH₂)_(x)(CONR₇(CH₂)_(y)CO₂R₉, (CH₂)_(x)(CONR₇(CH₂)_(y)CONR₇R₈,(CH₂)_(x)CONR₇(CH₂)_(y)R₉, (CH₂)_(x)COR₇, (CH₂)_(x)CO₂R₇,(CH₂)_(x)SO₂NR₇ (CH₂)_(y)R₉, CHR₇COR₉, CHR₇CONHCHR₈COR₉ CONR₇R₈, CONR₇(CH₂)_(x)CO₂R₈, CONR₇CHR₈CO₂R₉, NHCO₂R₇, or (CH₂)_(x)SO₂NR₇R₈.
 23. Thecompound of claim 21, wherein

is phenyl, pyridyl, or pyrimidinyl.
 24. The compound of claim 21,wherein

is phenyl.
 25. The compound of claim 21, wherein

is pyridyl.
 26. The compound of claim 21, wherein: n is 2 and each A isOCH₃ and F, respectively; n is 2 and each A is CF₃ and F, respectively;n is 2 and each A is Cl and F, respectively; or n is 1 and A is CF₃. 27.The compound of claim 21, wherein R₂ is optionally substituted C₃₋₈alkyl.
 28. The compound of claim 21, wherein R₂ is optionallysubstituted C₁₋₈ alkyl(C₃₋₈ cycloalkyl).
 29. The compound of claim 21,wherein R₂ is optionally substituted C₃₋₈ cycloalkyl.
 30. The compoundof claim 21, wherein R₂ is optionally substituted cyclopentyl.
 31. Thecompound of claim 21, wherein R₂ is optionally substituted heteroaryl.32. The compound of claim 21, wherein R₄ is optionally substituted C₁₋₈alkyl, C₂₋₈ alkenyl, C₃₋₈ cycloalkyl, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl(C₃₋₈cycloalkyl), C₁₋₈ alkyl(heteroaryl), or (CH₂)_(x)(NR₇R₈; R₅ isoptionally substituted adamantanyl, aryl, C₁₋₈ alkyl, C₁₋₈ alkylalcohol, C₁₋₈ alkyl amino, C₁₋₈ alkyl amido, C₂₋₈ alkyl(aryl), C₁₋₈alkyl(C₃₋₈ cycloalkyl), C₁₋₈ alkyl(C₃₋₈ cycloalkyl)-CO₂R₇, C₁₋₈alkyl(guanidinyl), C₁₋₈ alkyl(heteroaryl), C₁₋₈ alkyl(tetrazol-5-one),C₂₋₄ alkyl(heterocycloalkyl), C₁₋₈ alkyl(thioether), C₁₋₈ alkyl(thiol),C₂₋₈ alkenyl, C₂₋₈ alkenyl(aryl), C₂₋₈ alkenyl(heteroaryl), C₃₋₈alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-CO₂R₇, (CH₂)_(x)NR₇R₈,(CH₂)_(x)OR₇, (CH₂)_(x)NR₉COR₇, (CH₂)_(x)NR₉SO₂R₇, (CH₂)_(x)NR₉CO₂R₇,(CH₂)_(x)NHCOR₇, (CH₂)_(x)NHSO₂R₇, (CH₂)_(x)NHCO₂R₇, (CH₂)_(x)CONR₇R₈,(CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉, (CH₂)_(x)CONR₇(CH₂)_(y)CONR₇R₈,(CH₂)_(x)CONR₇(CH₂)_(y)R₉, (CH₂)_(x)COR₇, (CH₂)_(x)CO₂R₇,(CH₂)_(x)SO₂NR₇(CH₂)_(y)R₉, CHR₇COR₉, CHR₇CONHCHR₈COR₉, CONR₇R₈,CONR₇(CH₂)_(x)CO₂R₈, CONR₇CHR₈CO₂R₉, CO₂R₉, NHCO₂R₇, or(CH₂)_(x)SO₂NR₇R₈; and R₆ is H.
 33. The compound of claim 21, wherein R₄is optionally substituted C₁₋₈ alkyl(heteroaryl).
 34. The compound ofclaim 21, wherein R₅ is optionally substituted C₁₋₈ alkyl, aryl, C₁₋₈alkyl(aryl), C₁₋₈ alkyl(C₃₋₈ cycloalkyl). C₁₋₈ alkyl(heteroaryl), C₃₋₈cycloalkyl, (CH₂)_(x)NR₇R₈, (CH₂)_(x)NHCOR₇, (CH₂)_(x)NHCO₂R₇,(CH₂)_(x)CONR₇R₈, (CH₂)_(x)CONR₇(CH₂)_(y)CO₂R₉,(CH₂)_(x)CONR₇(CH₂)_(y)CONR₇R_(8,)(CH₂)_(x)CONR₇(CH₂)_(y)R₉,(CH₂)_(x)COR₇, (CH₂)_(x)CO₂R₇, CHR₇COR₉, CHR₇CONHCHR₈COR₉, or CONR₇R₈.35. The compound of claim 21, wherein R₇ and R₈ each are independentlyH, C₁₋₈ alkoxy, aryl, C₁₋₈ alkyl, C₁₋₈ alkyl alcohol, C₁₋₈ alkyl amino,C₁₋₈ alkyl amido, C₁₋₈ alkyl(aryl), C₁₋₈ alkyl (C₃₋₈ cycloalkyl), C₁₋₈alkyl tetrazol-5-one, C₁₋₈ alkyl guanidinyl, C₁₋₈ alkyl heteroaryl, C₁₋₈alkyl thioether, C₁₋₈ alkyl thiol, C₂₋₈ alkenyl, C₃₋₈ alkynyl, C₃₋₈cycloalkyl, (CH₂)_(x)CONHR₉, (CH₂)_(x)COR₉, (CH₂)_(x)CO₂R₉, orheteroaryl.